Oridonin analogs, compositions, and methods related thereto

ABSTRACT

Certain embodiments are directed to oridonin analogs or derivatives. In certain aspects, the derivatives are used as anticancer or anti-inflammatory agents.

This application is a continuation-in-part of and claims priority toInternational Application serial number PCT/US2014/03311 filed Apr. 5,2014 and U.S. provisional application 61/808,753 filed Apr. 5, 2013.Each of which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

This invention was made with government support under P30 DA028821awarded by the National Institute of Health. The government has certainrights in the invention.

BACKGROUND

Certain embodiments are directed to the fields of chemistry andoncology. Certain aspects are directed to anti-cancer andanti-inflammatory compounds.

Natural products have a profound impact upon both chemical biology anddrug discovery, and the great structural diversity of natural productsat various levels has always served medicinal chemists as a source ofinspiration in their search for new molecular entities withpharmacological activity (Newman, J. Med. Chem. 2008, 51:2589-99).Natural tetracyclic diterpenoids, especially ent-kaurane diterpenoidswith an enone system in ring D such as oridonin (1) and eriocalyxin B,constitute an important class of natural products which exhibitconsiderable pharmacological activities including anti-tumor andanti-inflammatory effects (Nagashima et al., Tetrahedron 2005,61:4531-44; Huang et al., J. Nat. Prod. 2005, 12:1758-62; Li et al.,Phytochemistry 2006, 13:1336-40).

Structurally, the highly oxygenated oridonin, belonging to 7,20-epoxy-ent-kaurane-type diterpenoid, is primarily characterized withan α,β-unsaturated ketone moiety in ring D and a 6-hydroxyl-7-hemiacetalgroup, which is stereochemically rich and densely functionalized. Todate, reported structure modifications are primarily focused on the 1-Oand 14-O positions, likely due to synthetic ease (Xu et al., Bioorg.Med. Chem. Lett. 2008, 18:4741-44). There remains a need for developmentof additional oridonin analogs.

SUMMARY

Oridonin is a natural product (isolated from the herb rabdosiarubescens) that is used in Chinese traditional medicine for itsantitumor, antibacterial, antiviral, and anti-inflammatory effects.Certain embodiments are directed to oridonin analogs or derivatives. Incertain aspects, the derivatives are used as anticancer oranti-inflammatory agents.

Certain embodiments are directed to compounds having the general formulaof Formula Ia, Ib, Ic, or Id:

where X is C or N; Y is C_(n) and n is 0, 1, 2, 3, 4, or 5; and R¹ andR² are independently hydrogen, oxo, nitro, halo, mercapto, cyano, azido,amino, imino, azo, —C(NH)(NH₂), sulfonyl, sulfinyl, sulfo, thioyl,methyl, ethyl, C2-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6carboxylate, C1-C6 carboxyl, C3-05 alkenyl, C2-C4 carbonyl, C2-C4aldehyde, C2-C8 heteroalkyl, C1-C6 alkylsulfonyl, C1-C6 alkylhalide,substituted or unsubstituted 3 to 8 membered cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycle, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl. In certain aspects, R¹and R² can optionally form a substituted or unsubstituted 3 to 8membered heterocyle or 3 to 9 membered cycloalkyl.

R³ and R⁴ are independently hydrogen, hydroxy, methyl, ethyl, C3-C5alkyl, C1-C5 hydroxyalkyl, a substituted or unsubstituted aryl, or asubstituted or unsubstituted heteroaryl.

Certain aspects are directed to compounds of Formula Ia where X is N; nis 0, 1, or 2; and R¹ is hydrogen. In a further aspect R² is hydrogen,C1-C4 alkyl, C2-C4 aldehyde, C1-C4 alkynyl (wherein the double bond isat C1-C2, C2-C3, or C3-C4), —C(NH)(NH₂), or 3 to 7 membered cycloalkyl.In certain aspect R¹ and R² form a 4 to 6 member cycloalkyl orheterocyclyl.

In certain aspects X is C, n is 0, and R¹ is hydrogen and R² ishydrogen, C1-C4 alkyl.

In certain aspects a compound of Formula I is(6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-2,5,5-trimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-19);(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-amino-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-5-41);(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-2-(methylamino)-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-5-54);(6S,7S,7aR,10R,12bR,15R)-2-(cyclohexylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-17-2);(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(allylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CTD-6-18);(6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-2-((2-(piperidin-1-yl)ethyl)amino)-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-20);N-((6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-8-oxo-5,5a,6,7,8,9,10,11,12,12a-decahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-2-yl)acetamide(CYD-6-21);(6S,7S,7aR,10R,12bR,15R)-2-(azepan-1-yl)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-26-2); (5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(butylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-28);1-((5aR,6S,7S,7aR,10S,12aS,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-8-oxo-5,5a,6,7,8,9,10,11,12,12a-decahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-2-yl)guanidine(CYD-6-29); or(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-6,7,15-trihydroxy-2-(isopropylamino)-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-30).

Certain aspects are directed to compounds of Formulas Ic or Id where Xis N; Y is C_(n) and n is 0, 1, 2, 3, or 4; R¹ is hydrogen; and R² ishydrogen, methyl, C2 alkenyl, or C6 cycloalkyl.

Certain embodiments are directed to compounds having the general formulaof Formula IIa or IIb or IIc or IId or IIe or IIf or IIg or IIh or IIior IIj:

where R⁵, R⁶, and R⁷ are independently hydrogen, oxo, nitro, halo,mercapto, cyano, azido, amino, imino, azo, sulfonyl, sulfinyl, sulfo,thioyl, methyl, ethyl, hydroxyl, NR⁸R⁹, C1-C6 carboxyl, C1-C6hydroxyalkyl, C1-C6 aldehyde, C2-C6 ketone, C1-C6 ester, C1-C6 alkyl,C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkenyl; C1-C6 alkylsulfonyl,substituted or unsubstituted 3 to 6 membered cycloalkyl, substituted orunsubstituted 3 to 6 membered heterocyclyl, substituted or unsubstitutedmembered aryl, substituted or unsubstituted membered heteroaryl,substituted or unsubstituted triazole, substituted or unsubstituted 3 to6 membered spiro-cycloalkyl, or substituted or unsubstituted 3 to 6membered spiro-heterocycle; and R⁸ and R⁹ are independently hydrogen,oxo, nitro, halo, mercapto, cyano, azido, amino, imino, azo, sulfonyl,sulfinyl, sulfo, thioyl, methyl, ethyl, hydroxyl, C1-C6 carboxyl, C1-C6hydroxyalkyl, C1-C6 aldehyde, C2-C6 ketone, C1-C6 ester, C1-C6 alkyl,C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkylsulfonyl,substituted or unsubstituted 3 to 8 membered cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted triazole, substituted or unsubstituted 3 to 6 memberedspiro-cycloalkyl, or substituted or unsubstituted 3 to 6 memberedspiro-heterocycle. In certain aspects the A ring is saturated, has adouble bond between positions 1 and 2, or has a double bond betweenpositions 2 and 3. In certain aspects R³ and R⁴ are as described abovefor Formula Ib.

In certain aspects the compound having R⁶ and R⁷ as hydrogen when R⁵ isoxo can be specifically excluded from compounds of Formula IIa, FormulaIIb, and Formula IId.

In certain aspects one or more of R⁵, R⁶, or R⁷ is oxo. In certainaspects R⁵, R⁶, or R⁷ are nitro, cyano, azido, amino, imino, azo, NR⁸R⁹,substituted or unsubstituted triazole, substituted or unsubstituted 3 to8 membered N containing heterocycle, or substituted or unsubstituted 3to 8 membered N containing heteroaryl, wherein R⁸ and R⁹ areindependently hydrogen or C1-C4 alkyl. In a further aspect a substitutedtriazole has an aryl or heteroaryl substituent. In certain aspects R⁵,R⁶, or R⁷ is substituted or unsubstituted spiro-tetrahydrofuran orspiro-furan. In a further embodiment the tetrahydrofuran or furancomprises a C1-C3 alkoxy substituent. In certain aspects the A ring issaturated, or has a double bond between positions 1 and 2, or has adouble bond between positions 2 and 3.

In certain aspects R⁵ and R⁶ of Formula IIc are as described for FormulaIIa with the exception that they cannot be substituted or unsubstitutedspiro-cycloalkyl, or substituted or unsubstituted spiro-heterocycle. R⁷,R⁸, and R⁹ are as described for Formula IIa.

In certain aspects R⁶ and R⁷ of Formula IId are as described for FormulaIIa with the exception that R⁶ and R⁷ cannot be substituted orunsubstituted spiro-cycloalkyl, or substituted or unsubstitutedspiro-heterocycle.

In certain aspects a compound of Formula II is(3S,3aR,3a¹R,6aR,7S,7aR,11aR,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-2,3,3a,7,7a,8,9,11b-octahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-6-75);(4aR,5S,6S,6aR,9S,11aS,11bR,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one(CYD-6-82);(3S,3aR,3a¹R,6aR,7S,7aS,9S,11aR,11bS)-7,9-dihydroxy-5,5,8,8-tetramethyl-15-methylene-2,3,3a,7,7a,8,9,11b-octahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-6-81);(3S,4aS,5S,6S,6aR,9S,11aS,11bR,14R)-3,5,6,14-tetrahydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one(CYD-6-90);(3S,3aR,3a¹R,6aR,7S,7aS,11aR,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-3,3a,7,7a,8,11b-hexahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-9,14(2H)-dione(CYD-6-86);(4aS,5S,6S,6aR,9S,11aS,11bR,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-3,7(8H)-dione(CYD-6-93);(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS,Z)-10-((dimethylamino)methylene)-7-hydroxy-5,5,8,8-tetramethyl-15-methyleneoctahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-11,14(2H)-dione(CYD-6-77);(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS,Z)-7-hydroxy-10-(hydroxymethylene)-5,5,8,8-tetramethyl-15-methyleneoctahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-11,14(2H)-dione (CYD-6-91);(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-11,14-dioxo-2,3,3a,7,7a,8,11,11b-octahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-10-carbaldehyde (CYD-6-92);(1aR,3aR,4S,5S,5aR,8S,10aS,10bS,10cS,13R)-4,5,13-trihydroxy-3,3-dimethyl-7-methylenedecahydro-1aH-5,10b-(epoxymethano)-5a,8-methanocyclohepta[7,8]naphtho[1,2-b]oxiren-6(2H)-one(CYD-7-23-1) and(1S,2S,4aR,5S,6S,6aR,9S,11aS,11bS,14R)-1,2,5,6,14-pentahydroxy-4,4-dimethyl-8-methylenedecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one(CYD-7-23-2);(3S,3aR,3a¹R,6aR,7S,7aR,10S,11S,11aS,11bS)-10-azido-7,11-dihydroxy-5,5,8,8-tetramethyl-15-methylenedecahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-42); or(3S,3aR,3a¹R,6aR,7S,7aR,10S,11S,11aS,11bS)-7,11-dihydroxy-5,5,8,8-tetramethyl-15-methylene-10-(4-phenyl-1H-1,2,3-triazol-1-yl)decahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-54).

Certain aspects are directed to compounds of Formula IIe or IIf or IIgor IIh or IIi, or IIj where R⁵ is a hydrogen or hydroxyl or carbonyl; R⁶is hydrogen; and and R⁷ is hydrogen or a carbonyl.

Certain embodiments are directed to compounds having the general formulaof Formula IIIa or IIIb:

where ring E is a substituted or unsubstituted 3 to 8 memberedheterocycle having 1, 2, or 3 heteroatoms; substituted or unsubstituted3 to 8 membered cycloalkyl; substituted or unsubstituted aryl;substituted or unsubstituted heteroaryl having 1, 2, or 3 heteroatoms;and R⁷ is hydrogen, hydroxyl, oxo, nitro, halo, mercapto, cyano, azido,amino, imino, azo, sulfonate ester, sulfonyl, sulfinyl, sulfo, thioyl,methyl, ethyl, C3-C5 alkyl, C3-C5 alkenyl, C2-C4 ketone, substituted orunsubstituted 3 to 8 membered cycloalkyl, substituted or unsubstituted 3to 8 membered heteroalkyl. In certain aspects ring A is saturated, orhas a double bond between the 1 and 2 position or the 2 and 3 position.In certain aspects R⁷ can optionally form a polycyclic moiety with ringE.

In certain aspects the E ring is a substituted or unsubstituted 3 to 8membered heterocycle having 1, 2, or 3 heteroatoms. In other aspects theE ring is a substituted or unsubstituted heteroaryl having 1, 2, or 3heteroatoms.

In a further aspect the E ring is substituted or unsubstitutedaziridine, azirine, oxirane (epoxide), oxirene, thirane, thirene,azetidine, oxetane, thietane, azete, oxete, thiete, diazetidine,dioxetane, ditietane, pyrrolidine, pyrrole, tetrahydrofuran, furan,thiolane, thiophene, priperidine, pyridine, oxane, pyran, thiane,thiopuran, imidazole, imidazolidine, oxazolidine, oxazoledioxalane,triazole, oxadiazole, or thiodiazole. In certain aspects the E ring isan oxo substituted thiete.

In certain aspects R⁷ is sulfonate ester. In a further aspect thesulfonate ester is bonded to the E ring forming a polycyclic moiety.

In certain aspects a compound of Formula III is(1aR,3aR,4S,4aR,4a¹R,7aR,8S,10aS,10bS,10cS)-4-hydroxy-3,3,6,6-tetramethyl-13-methylenedecahydro-1aH-4a,10b-(epoxymethano)-4a¹,8-ethanooxireno[2′,3′:5,6]phenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-9);(1aR,2R,3aR,4S,4aR,4a¹R,7aR,8S,10aS,10bS,10cS)-2,4-dihydroxy-3,3,6,6-tetramethyl-13-methylenedecahydro-1aH-4a,10b-(epoxymethano)-4a¹,8-ethanooxireno[2′,3′:5,6]phenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-19); or(1aR,2R,3aR,4S,5S,5aR,8S,10aS,10bS,10cS,13R)-2,4,5,13-tetrahydroxy-3,3-dimethyl-7-methylenedecahydro-1aH-5,10b-(epoxymethano)-5a,8-methanocyclohepta[7,8]naphtho[1,2-b]oxiren-6(2H)-one(CYD-7-27).

Certain embodiments are directed to compounds having the general formulaof Formula IVa or IVb:

where ring E is as described in Formula IIIa. R⁵ is hydrogen, hydroxyl,oxo, nitro, halo, mercapto, cyano, azido, amino, imino, azo, sulfonateester, sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, C3-C5 alkyl,C3-C5 alkenyl, C2-C4 ketone, substituted or unsubstituted 3 to 8membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheteroalkyl. Ring A has no double bonds, a double bond between the 1 and2 position, or the 2 and 3 position. In certain aspects R⁵ canoptionally form a polycyclic moiety with ring E. In certain aspects R³and R⁴ are as described for Formula Ib.

In a further aspect the E ring is substituted or unsubstitutedaziridine, azirine, oxirane (epoxide), oxirene, thirane, thirene,azetidine, oxetane, thietane, azete, oxete, thiete, diazetidine,dioxetane, ditietane, pyrrolidine, pyrrole, tetrahydrofuran, furan,thiolane, thiophene, priperidine, pyridine, oxane, pyran, thiane,thiopuran, imidazole, imidazolidine, oxazolidine, oxazoledioxalane,triazole, oxadiazole, or thiodiazole. In certain aspects the E ring isan oxo substituted thiete.

Certain embodiments are directed to compounds having the general formulaof Formula Va or Vb or Vc or Vd:

where R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ areindependently hydrogen, oxo, nitro, halo, mercapto, cyano, azido, amino,imino, azo, sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, hydroxyl,C1-C6 carboxyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6alkenyl, C1-C6 alkylsulfonyl, substituted or unsubstituted 3 to 8membered cycloalkyl, or substituted or unsubstituted 3 to 8 memberedheterocyclyl. R³, R³′, R⁴ and R⁴′ are as described for R³ and R⁴ inFormula Ib.

In certain aspects R¹⁸ and R¹⁹ can bridged by an oxygen to form anepoxide.

In certain aspects a compound of Formula V is(2R,4aR,5S,6S,6aR,6a′R,7′S,8′S,8a′R,9S,11aS,11bS,11′S,13a′S,13b′S,14R,16′R)-5,6,7′,8′,14,16′-hexahydroxy-4,4,6′,6′-tetramethyl-8,10′-dimethylene-4,4a,5,6,6′,6a′,7′,8′,9,10,11,11a,11′,12′,13′,13a′-hexadecahydro-3′H-spiro[6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-2,2′-8,13b-(epoxymethano)-8a,11-methanocyclohepta[3,4]benzo[1,2-h]chromene]-1,7,9′(3H,4′H,5′H,8H,10′H)-trione(CYD-5-40-2), or(2R,4aR,4a′R,5′S,6aR,6′S,6a′R,7S,8S,8aR,9′S,11S,11a′S,11b′S,13aS,13bS,13cR,14′R,17R)-5′,6′,7,8,14′,17-hexahydroxy-4′,4′,6,6-tetramethyl-8′,10-dimethylenehexadecahydro-3H-spiro[4a,13c-epoxy-8,13b-(epoxymethano)-8a,11-methanocyclohepta[3,4]benzo[1,2-h]chromene-2,2′-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene]-1′,7′,9(3′H,4H,5H,8′H,10H)-trione(CYD-6-39).

Certain embodiments are directed to compounds having the general formulaof Formula VIa or VIb:

where R¹⁰, R¹¹, R¹², R²⁰, and R²¹ are independently hydrogen, oxo,nitro, halo, mercapto, cyano, azido, amino, imino, azo, carbamoyl,sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, hydroxyl, C1-C6carboxyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkenyl,C1-C6 alkylsulfonyl, substituted or unsubstituted 3 to 8 memberedcycloalkyl, or substituted or unsubstituted 3 to 8 memberedheterocyclyl. In certain aspects R²⁰ and R²¹ can optionally form asubstituted or unsubstituted 3 to 8 membered cycloalkyl, or substitutedor unsubstituted 3 to 8 membered heterocyclyl. R³ and R⁴ are asdescribed for Formula Ib.

Certain embodiments are directed to compounds having the general formulaof Formula VIIa or VIIb:

where V is O or NR²²; R¹⁰, R¹¹, and R¹² are as described in Formula VI;and R²² is hydrogen, oxo, nitro, halo, mercapto, cyano, azido, amino,imino, azo, sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, hydroxyl,C1-C6 carboxyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6alkenyl, C1-C6 alkylsulfonyl, substituted or unsubstituted 3 to 8membered cycloalkyl, or substituted or unsubstituted 3 to 8 memberedheterocyclyl. R³ and R⁴ are as described for Formula Ib.

Other embodiments of the invention are discussed throughout thisapplication. Any embodiment discussed with respect to one aspect of theinvention applies to other aspects of the invention as well and viceversa. Each embodiment described herein is understood to be embodimentsof the invention that are applicable to all aspects of the invention.

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The terms “comprise,” “have,” and “include” are open-ended linkingverbs. Any forms or tenses of one or more of these verbs, such as“comprises,”“comprising,”“has,” “having,” “includes,” and “including,”are also open-ended. For example, any method that “comprises,”“has,” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

As used herein, the term “IC₅₀” refers to an inhibitory dose thatresults in 50% of the maximum response obtained.

The term half maximal effective concentration (EC₅₀) refers to theconcentration of a drug that presents a response halfway between thebaseline and maximum after some specified exposure time.

The terms “inhibiting,” “reducing,” or “prevention,” or any variation ofthese terms, when used in the claims and/or the specification includesany measurable decrease or complete inhibition to achieve a desiredresult.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

As used herein, the term “patient” or “subject” refers to a livingmammalian organism, such as a human, monkey, cow, sheep, goat, dogs,cat, mouse, rat, guinea pig, or species thereof. In certain embodiments,the patient or subject is a primate. Non-limiting examples of humansubjects are adults, juveniles, infants and fetuses.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofthe specification embodiments presented herein.

FIG. 1. Representative molecules of the tetracyclic diterpenes.

FIG. 2. Aqueous solubility of oridonin analogs. Compounds 7 (CYD-6-19),14 (CYD-6-18) and 8 (CYD-5-54) showed significantly improved solubilitycompared with oridonin. Compounds 14 (HCl salt) and 8 (HCl salt) aresoluble in water at a concentration of 42.38 mg/mL and 81.15 mg/mL,respectively, which are approximately 32- and 62-fold better thanoridonin (1.29 mg/mL).

FIG. 3. Effects of oridonin and its analogues on growth indrug-resistant MCF-7 cells.

FIG. 4. Effects of oridonin and its analogues on growth in mammaryepithelial MCF-10A cells.

FIG. 5. Structures of molecules of Formula I.

FIG. 6. Structures of molecules of Formula II.

FIG. 7. Structures of molecules of Formula III.

FIG. 8. Structures of molecules of Formula IV.

FIG. 9. Structures of molecules of Formula V.

FIG. 10. Structures of molecules of Formula VI.

FIG. 11. Structures of molecules of Formula VII.

FIG. 12. Illustrates the substrate scope of one-pot cross-HAD reactionswith various vinyl ether and vinyl sulfide.

FIG. 13. In vivo efficacy of oridonin and compound CYD0618 in inhibitinggrowth of xenograft tumors (breast cancer MDA-MB-231) in mice (i.p.) atthe dose of 5 mg/kg, respectively. Data are presented as the mean±SE oftumor volume at each time point; Significant differences betweencompound CYD0618 treatment group, oridonin treatment group and controlwere determined using one way ANOVA. p<0.0001.

FIG. 14. In vivo therapeutic efficacy of compound CYD0686 compared tooridonin in inhibiting growth of xenograft tumors (triple-negativebreast cancer cell line MDA-MB-231) in mice (i.p.) at 5 mg/kg: (A)average tumor size changes; (B) average body weight changes. Values aremean±SE of three independent experiments. Statistical significance wasdetermined using one-way ANOVA (p<0.0001).

FIG. 15. Oridonin derivatives comprising an aziridine group.

DESCRIPTION

I. Oridonin and Related Compounds

Oridonin, an ent-kaurane diterpenoid isolated from plants of genusIsodon (Rabdosia), has been widely used by the local people in China forthe treatment of respiratory and gastrointestinal bacterial infections,inflammation, and various cancers for many years (Fujita et al., Chem.Pharm. Bull. 1976, 24(9):2118-27; Yin et al., J. Chin. Pharm. Univ.2003, 34, 302-4). Of particular interest is its unique, safe anticancerpharmacological profile (Abelson, Science 1990, 247:513-15). Increasingevidence has suggested that oridonin may improve the survival rates ofcancer patients through hampering the progression of tumor, mitigatingtumor burden, and alleviating cancer syndrome (Li et al., TheInternational Journal of Biochemistry & Cell Biology. 2011, 43:701-04).For example, oridonin not only induced typical mitochondrial apoptosisin acute myeloid leukemic cells with an IC₅₀ value of 2 μM, but alsoexhibited substantial anti-leukemia activities with a low side-effect inmurine models (15 mg/kg) (Zhou et al., Blood 2007, 109:3441-50).Oridonin was also demonstrated to inhibit tumor cell proliferation andinduce cancer cell death by regulating a series of transcriptionfactors, protein kinases as well as pro- and/or anti-apoptotic proteins(Li et al., The International Journal of Biochemistry & Cell Biology.2011, 43:701-04; Zhang et al., Chin. Pharm. 1 2003, 38:817-20; Huang etal., J. Nat. Prod. 2005, 12:1758-62). However, its relatively moderatepotency, limited aqueous solubility, and bioavailability hamperedoridonin use in the clinic (Zhang et al., Chin. Pharm. J. 2003,38:817-20; Xu et al., Acta Pharmacologica Sinica 2006, 27(12):1642-46).

Oridonin has elicited a great deal of interest due to its biologicalrole, safe pharmacological profile, and its densely functionalized,stereochemistry-rich frameworks. The inventors have taken advantage oforidonin, a naturally abundant and large-scale commercially availableent-kaurane diterpenoid, as a basic template to construct a naturalproduct-like compound library through diversity-oriented synthesis foridentifying anti-cancer drugs. A compound library of novel oridoninanalogs have been designed, synthesized and pharmacologically evaluatedby following approaches including, but not limited to oridonin ringA-based diversity-oriented synthesis including enone functionalization,heteroaromatic cycle-fused construction, ring expansion and contraction,and diversity-oriented functionalization at C-14 position.

Oridonin analogs are described herein. The analogs described can be usedfor the treatment of human cancer and inflammation. A series of oridoninanalogs have been synthesized and tested in breast, pancreatic, andprostate cancer cell lines. A number of the compounds are effective insuppressing cell growth. The molecules described herein may be used aspreventive and therapeutic agents for various cancers including but notlimited to breast cancers, pancreatic cancer, brain tumors, head/neckcancer, prostate and lung cancers, as well as inflammation.

A series of nitrogen-containing oridonin analogs with thiazole-fusedring A were prepared starting from oridonin through a protectinggroup-free synthetic strategy. Incorporating a substitutedthiazole-fused moiety into oridonin not only enhanced the anticanceractivity, but also significantly improved aqueous solubility. Most ofthese analogs such as compounds CYD-5-54, CYD-6-30, CYD-6-28,CYD-6-17-2, and CYD-6-18 have exhibited potent anti-proliferationeffects against cancer cell lines, especially breast cancer cellsincluding estrogen receptor (ER)-negative breast cancer cell MDA-MB-231,with low micromolar to nanomolar IC₅₀ values (Table 1).

TABLE 1a Effects of oridonin analogues on proliferation of human breast,pancreatic cancer and prostate cancer cell lines. IC₅₀ (μM)^(a) Breastcancer Prostate MDA-MB- Pancreatic cancer cancer Compound StructureMCF-7 231 AsPC1 Panc-1 DU145 Oridonin

6.64 29.42 34.47 13.37 14.23 CYD-6-19

2.63 6.88 6.46 7.83 7.63 CYD-5-41

1.02 3.24 5.58 6.13 3.46 CYD-5-54

1.28 2.06 1.84 2.33 4.05 CYD-6-30

0.82 0.28 1.45 3.27 5.31 CYD-6-28

0.59 1.06 1.39 4.01 4.22 CYD-6- 17-2

0.94 0.83 1.65 3.74 1.82 CYD-6- 26-2

1.15 6.82 2.30 6.29 4.74 CYD-6-20

1.00 1.83 1.10 1.54 1.16 CYD-6-18

0.18 0.18 1.05 1.1 1.18 CYD-6-21

1.99 6.82 4.83 6.71 6.34 CYD-6-29

3.43 >10^(b) >10 15.44 35.86 ^(a)Breast cancer cell lines: MCF-7,MDA-MB-231. Pancreatic cancer cell lines: ASPC1, MiaPaCa-2 and Panc-1.Prostate cancer: DU145. Software: MasterPlex ReaderFit 2010, MiraiBio,Inc. ^(b)If a specific compound is given a value >10, indicates that aspecific IC₅₀ cannot be calculated from the data points collected,meaning ‘no effect’.

TABLE 1b Antiproliferative effects of representative triazolesubstitutedanalogues against human breast cancer cell lines IC₅₀ (μM)^(a) CompoundsMCF-7 MDA-MB-231 Oridonin 6.6 29.4

0.38 0.48 CYD-7-86

2.1 1.8 CYD-7-90

2.3 1.8 CYD-7-82

2.0 1.1 CYD-8-3

1.9 3.5 CYD-8-5 ^(a)Breast cancer cell lines: MCF-7 and MDA-MB-231.Software: MasterPlex ReaderFit 2010, MiraiBio, Inc. Values are mean ± SEof three independent experiments.

TABLE 1c Antiproliferative Effects of Oridonin and the Dienone Analoguesagainst Human Breast Cancer Cell Lines MDA- Compound MCF-7 MB-231Oridonin 4.36 ± 1.41 28.0 ± 1.40

0.56 ± 0.31 3.49 ± 1.21 CYD-6-25

1.31 ± 0.25 2.23 ± 0.68 CYD-6-58

1.28 ± 0.47 3.46 ± 1.33 CYD-6-92

10.2 ± 3.07 >30 CYD-7-13

>30 >30 CYD-7-5

0.98 ± 0.19  5.6 ± 1.06 CYD-6-86

3.48 ± 2.16 9.39 ± 0.48 CYD-6-93 ^(a)Breast cancer cell lines: MCF-7 andMDA-MB-231. Software: MasterPlex ReaderFit 2010, MiraiBio, Inc. Valuesare the mean ± SE of three independent experiments. If a specificcompound is given a value >30, it indicates that a specific IC50 cannotbe calculated from the data points collected, meaning “no effect”.

TABLE 1d Growth Inhibitory Effects of Oridonin and the Selected DienoneAnalogues against Drug-Resistant Breast Cancer MCF-7/ADR Cells CompoundIC50 (μM)^(a) Oridonin >30

5.03 ± 1.91 CYD-6-25

5.82 ± 2.12 CYD-6-58

6.55 ± 0.96 CYD-6-92

6.02 ± 1.28 CYD-6-86 ^(a)Breast cancer cell line: MCF-7/ADR. Software:MasterPlex ReaderFit 2010, MiraiBio, Inc. Values are the mean ± SE ofthree independent experiments. If a specific compound is given avalue >30, it indicates that a specific IC50 cannot be calculated fromthe data points collected, meaning “no effect”.

Moreover, these thiazole-fused oridonin derivatives have improvedaqueous solubility in comparison with oridonin. The aqueous solubilityof analog CYD-6-19 with 2-methyl thiazole moiety was determined to be4.47 mg/mL, and the N-alkyl derivatives CYD-6-18 and CYD-5-54 in theform of HCl salt demonstrated a solubility with a saturatedconcentration of 42.38 mg/mL and 81.15 mg/mL, respectively, indicating32-fold to 62-fold improvement in comparison with that of oridonin (1.29mg/mL) (FIG. 2). Some other analogs such as compounds CYD-6-20 andCYD-6-29 (HCl salt) possess an even superior aqueous solubility greaterthan 100 mg/mL.

A number of dienone analogs such as CYD-6-86, and CYD-6-92 have beenidentified with potent anti-proliferation effects against breast,pancreatic, and prostate cancer cell lines with low micromolar tonanomolar IC₅₀ values (Table 2). Moreover, oridonin analogs describedherein significantly induce apoptosis against estrogen receptor(ER)-negative including triple-negative, and drug-resistant breastcancer cells (FIG. 3), while displayed less toxicity towards mammaryepithelial cells (FIG. 4) when compared with oridonin.

TABLE 2a Effects of A-ring modified oridonin analogues on proliferationof human breast, pancreatic cancer and prostate cancer cell lines. IC₅₀(μM)^(a) Breast cancer MDA- Pancreatic cancer Compound Structure MCF-7MB-231 AsPC1 Panc-1 Oridonin

6.64 29.42 34.47 13.37 CYD-6-75

0.95 3.95 6.78 7.25 CYD-6-82

0.79 3.90 1.09 1.19 CYD-6-25

1.10 5.60 8.82 7.93 CYD-6-58

0.95 3.56 2.99 >10 CYD-6-81

2.56 10.49 >10^(b) 5.24 CYD-6-90

1.21 26.06 >10 >10 CYD-6-86

0.86 4.39 0.81 6.49 CYD-6-93

0.71 10.29 10.17 9.67 CYD-6-77

9.07 164.63 11.81 >10 CYD-6-92

1.46 6.09 3.57 5.35 CYD-7-5

>10 >10 >10 >10 CYD-5-40- 2

4.82 9.64 10.21 8.07 CYD-6-39

>10 >10 104.21 >10 ^(a)Breast cancer cell lines: MCF-7, MDA-MB-231.Pancreatic cancer cell lines: ASPC1, MiaPaCa-2 and Panc-1. Software:MasterPlex ReaderFit 2010, MiraiBio, Inc. ^(b)If a specific compound isgiven a value >10, indicates that a specific IC₅₀ cannot be calculatedfrom the data points collected, meaning ‘no effect’.

TABLE 2b Effects of New Oridonin Analogues on Proliferation of HumanBreast (MCF-7 and MDA-MB-231), Pancreatic Cancer (AsPC1 and Panc-1), andProstate Cancer (DU145) Cells. MCF-7 (ER MDA-MB-231 Compound positive)(ER negative) AsPC1 Panc-1 DU145 Oridonin 6.6 29.4 19.3 15.6 14.2

1.0 3.2 5.6 6.1 3.5 R¹ = R² = H

2.6 6.9 6.5 7.8 7.6 CYD-6-19

1.3 2.1 1.8 2.3 4.1 CYD-5-54

0.8 0.3 1.4 3.3 5.3 CYD-6-30

0.6 1.1 1.4 4.0 4.2 CYD-6-28

0.9 0.8 1.7 3.7 1.8 CYD-6-17-2

1.2 6.8 2.3 6.3 4.7 CYD-6-26-2

1.0 1.8 1.1 1.5 1.2 CYD-6-20

0.2 0.2 1.1 1.1 1.2 CYD-6-18

2.0 6.8 4.8 6.7 6.3 CYD-6-21

3.4 >10^(b) >10 >10 >10 CYD-6-29 ^(a)Breast cancer cell lines: MCF-7 andMDA-MB-231. Pancreatic cancer cell lines: AsPC1 and Panc-1. Prostatecancer cell line: DU145. Software: MasterPlex ReaderFit 2010, MiraiBio,Inc. The values are the mean ± SE of at least three independentexperiments. ^(b)If a specific compound is given a value >10, itindicates that a specific IC50 cannot be calculated from the data pointscollected, meaning “no effect”.

To further develop oridonin derivatives with anticancer potency and/orsolubility, a sizable compound library of oridonin analogs is beingsynthesized through diversity-orientated synthesis (FIG. 5).

II. Cancer Therapy

The small molecules described herein can be developed as highly potentand orally active agents for the prevention and treatment of variouscancers including but not limited to breast cancers, pancreatic cancer,brain tumors, head/neck cancer, prostate and lung cancers as well asinflammation. Although a large portion of ER-positive breast cancer canbe prevented and treated with ER modulators (such as tamoxifen andraloxifene) and aromatase inhibitors (such as anastrozole and letrozole)as preventive and therapeutic drug, these available drugs fail toprevent the rest ER-positive breast cancers (approximately 45% of allER-positive) and all ER-negative breast cancers (both accounting forapproximately 60% of all breast cancer cases, including triple-negativebreast cancer). In particular, ER-negative breast cancer includingtriple negative breast cancer does not respond to hormonal therapy andis inclined to develop metastasis. Thus, effective targets and agentsare needed to prevent and treat the resistant ER-positive breast cancerand all ER-negative breast cancers, including triple negative breastcancers.

Through the medicinal chemistry efforts described herein combined withbiological characterization, a number of oridonin analogs have beenidentified with not only enhanced anticancer activity, but alsosignificantly improved aqueous solubility. These analogs havedemonstrated anti-proliferation effects against cancer cell lines,especially breast cancer cells, including estrogen receptor(ER)-negative breast cancer cell MDA-MB-231 with low micromolar tonanomolar IC₅₀ values. In addition, the analogs are found more effectiveon resistant cancer cells and less toxic to normal cells than isoridonin.

Molecules described herein may have better potency, efficacy, anddrug-like properties such as water solubility and bioavailability. Someanalogs may overcome resistance and provide a better cancer therapy. Thesmall molecules described herein can be developed as highly potent andorally active agents for the prevention and treatment of various cancersincluding but not limited to breast cancers, pancreatic cancer, braintumors, head/neck cancer, prostate and lung cancers, as well asinflammation.

In Vitro Determination of Effects of Synthesized Diterpenoids on CancerCell Proliferation. Breast cancer cell lines MCF-7, MDA-MB-231,MDA-MB-486 and MCF/ADR were seeded in 96-well plates at a density of1×104 cells/well and treated with DMSO and 0.01, 0.1, 1, 5, 10, and 100μM of individual compound for 48 h, and then 20 μL of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (5mg/mL in PBS) was added to each well and further incubated for another 4h. Then MTT solution was removed, and 150 μL of DMSO was added to eachwell. Absorbance of all wells was determined by measuring OD at 550 nmafter a 10 min incubation on a 96-well GlowMaxate absorbance reader(Promega, Madison, Wis.). Each individual compound was tested inquadruplicate wells for each concentration.

The growth inhibitory effects of the newly generated pyran-fusedditerpenoids were evaluated in four breast cancer cell lines MCF-7(ER-positive), MDAMB-231 (ER-negative and triple-negative), MDA-MB-468(ER-negative and triple-negative) as well as MCF-7/ADR(adriamycin-resistant) using MTT assays as described in the ExperimentalSection. The capability of these new molecules to inhibit the growth ofcancer cells was summarized in Table 3 and compared with that ofadriamycin and 1 spontaneously. Most of these new compounds not onlyexhibited significantly improved antiproliferative effects on breastcancer MCF-7, MDA-MB-468, and MDA-MB-231 cells relative to 1, but alsodisplayed marked growth inhibitory activity against drug-resistantbreast cancer MCF-7/ADR cells.

TABLE 3 Antiproliferative effects of pyran-fused diterpenoids againsthuman breast cancer cells. IC₅₀ (μM)^(a) Compounds MCF-7 MDA-MB-231MDA-MB-468 MCF-7/ADR Oridonin 4.36 ± 1.41 28.0 ± 1.40 5.33 ± 1.36 34.79± 2.54 Adriamycin 0.67 ± 0.45 2.33 ± 0.22 0.65 ± 0.26 >10^(b)

2.41 ± 1.45 2.23 ± 0.39 2.98 ± 0.67  3.80 ± 1.15 CYD-8-69-1

2.41 ± 1.86 3.73 ± 0.28 5.81 ± 1.92  6.79 ± 3.46 CYD-8-69-2

3.52 ± 2.15 6.13 ± 2.43 5.40 ± 0.98  4.65 ± 3.15 CYD-8-45-1

0.44 ± 0.27 0.54 ± 0.14 0.52 ± 0.18  1.64 ± 0.72 CYD-8-45-2

2.24 ± 1.33 1.76 ± 0.22 2.62 ± 0.08  4.42 ± 0.90 CYD-8-52-1

5.83 ± 3.75 8.18 ± 0.57 6.95 ± 1.01 10.31 ± 1.65 CYD-8-52-2

4.32 ± 1.82 7.12 ± 0.22 4.89 ± 0.85  4.31 ± 2.43 CYD-8-66-1

2.10 ± 0.98 3.30 ± 0.23 4.37 ± 1.48  3.19 ± 0.54 CYD-8-66-2

2.31 ± 1.02 3.30 ± 1.81 2.99 ± 1.01  3.08 ± 1.12 CYD-8-65-1

6.76 ± 3.43 7.15 ± 1.27 7.26 ± 0.23  8.74 ± 0.27 CYD-8-65-2

2.14 ± 1.11 3.18 ± 0.24 2.65 ± 0.14  4.51 ± 1.54 CYD-8-67-1

5.17 ± 2.90 5.89 ± 2.04 5.96 ± 0.29  5.34 ± 1.29 CYD-8-67-2

2.30 ± 1.40 2.87 ± 0.54 2.83 ± 0.42  3.82 ± 0.47 CYD-8-84

7.79 ± 3.18 7.57 ± 0.44 6.63 ± 0.77  8.60 ± 0.70 CYD-8-87

2.39 ± 0.78 2.53 ± 0.77 3.33 ± 0.58  2.89 ± 0.32 CYD-8-74-2

1.90 ± 0.97 3.32 ± 1.01 2.24 ± 0.68  3.18 ± 0.89 CYD-8-50 ^(a)Software:MasterPlex ReaderFit 2010, MiraiBio, Inc. Values are the mean ± SE ofthree independent experiments. ^(b)If a specific compound is given avalue >10, it indicates that a specific IC₅₀ cannot be calculated fromthe data points collected, meaning “no effect”.

Compound CYD-6-18 Suppressed Growth of Xenograft Tumors in Nude Mice. Inpilot in vivo studies, this compound was further evaluated for itsanticancer activity in suppression of tumor growth in thetriple-negative breast cancer MDA-MB-231 xenograft model. As shown inFIG. 13, mice treated with 5.0 mg/kg of compound CYD-6-18 via ip showeda much better effect in inhibiting tumor growth as compared to the micetreated with the same dose of oridonin (p<0.0001). The compound wasfound to be tolerated during the experiments and showed no significantloss of body weight (data not shown). These findings suggest thatcompound CYD-6-18 is a promising anticancer drug candidate with potentantitumor activity and excellent aqueous solubility for further clinicdevelopment.

Compound CYD-6-86 Suppressed Growth of Xenograft Tumors in Mice. In invivo studies, dienone analog CYD-6-86 was further evaluated for itsantitumor activity in suppression of tumor growth in the triple-negativeMDA-MB-231 xenograft model because of its potent antiproliferative andcolony formation inhibitory effects in MDA-MB-231 cells as well as lowertoxicity in HMEC cells. The compound was selected for further in vivoefficacy studies because of its good in vitro dose-responserelationship. As shown in FIG. 14A, compound CYD-6-86 at 5.0 mg/kg wasmuch more efficacious in suppressing xenograft tumor growth as comparedto oridonin at the same dosage (p<0.0001). The compound was also foundto be well tolerated during experiments and showed no significant lossof body weight (FIG. 14B). These results suggest that compound CYD-6-86is a promising anticancer drug candidate with potent antitumor activityand good tolerability for further clinical development.

III. Chemical Definitions

Various chemical definitions related to such compounds are provided asfollows.

As used herein, “predominantly one enantiomer” means that the compoundcontains at least 85% of one enantiomer, or more preferably at least 90%of one enantiomer, or even more preferably at least 95% of oneenantiomer, or most preferably at least 99% of one enantiomer.Similarly, the phrase “substantially free from other optical isomers”means that the composition contains at most 5% of another enantiomer ordiastereomer, more preferably 2% of another enantiomer or diastereomer,and most preferably 1% of another enantiomer or diastereomer.

As used herein, the term “water soluble” means that the compounddissolves in water at least to the extent of 0.010 mole/liter or isclassified as soluble according to literature precedence.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York,1991).

As used herein, the term “nitro” means —NO₂; the term “halo” designates—F, —Cl, —Br or —I; the term “mercapto” means —SH; the term “sulfonateester” means —OSO₂R′, the term “cyano” means —CN; the term “azido” means—N₃; the term “imino” means ═NH; the term “azo” means —RN═NR; the term“thioyl” means —SH; the term “sulfonyl” means —SO₂R; The term “sulfinyl”means —S(O)R; the “sulfo” means —SO₃; the term “silyl” means —SiH₃, theterm “hydroxy” means —OH, and the term “hydroxyalkyl” means —ROH.

The term “amino” means a group having the structure —NR′R″ (the termincludes primary, secondary, and tertiary amines), the term “amide”means —C(O)NR′R″, R′ and R″ are independently hydrogen or an optionallysubstituted alkyl, heteroalkyl, cycloalkyl, or heterocyclyl group.

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a linear (i.e. unbranched) or branched carbonchain, which may be fully saturated, mono- or polyunsaturated. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Saturated alkyl groups include those having one or morecarbon-carbon double bonds (alkenyl) and those having one or morecarbon-carbon triple bonds (alkynyl). The groups, —CH₃ (Me), —CH₂CH₃(Et), —CH₂CH₂CH₃ (n-Pr), —CH(CH₃)₂ (iso-Pr), —CH₂CH₂CH₂CH₃ (n-Bu),—CH(CH₃)CH₂CH₃ (sec-butyl), —CH₂CH(CH₃)₂ (iso-butyl), —C(CH₃)₃(tent-butyl), —CH₂C(CH₃)₃ (neo-pentyl), are all non-limiting examples ofalkyl groups.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a linear or branched chain having atleast one carbon atom and at least one heteroatom selected from thegroup consisting of O, N, S, P, and Si. In certain embodiments, theheteroatoms are selected from the group consisting of O, and N. Theheteroatom(s) may be placed at any interior position of the heteroalkylgroup or at the position at which the alkyl group is attached to theremainder of the molecule. Up to two heteroatoms may be consecutive. Thefollowing groups are all non-limiting examples of heteroalkyl groups:trifluoromethyl, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CF₃,—CH₂OC(O)CH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂Cl, —CH₂CH₂OH,CH₂CH₂OC(O)CH₃, —CH₂CH₂NHCO₂C (CH₃)₃, and —CH₂Si(CH₃)₃.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.Alkenyl or alkynyl are optionally substituted.

The term “alkylsulfonyl” as used herein means a moiety having theformula —S(O₂)—R′, where R′ is an alkyl group. R′ may have a specifiednumber of carbons (e.g. “C₁₋₄ alkylsulfonyl”). Alkyl sulfonyl isoptionally substituted.

The term “alkoxy” means a group having the structure —OR′, where R′ isan optionally substituted alkyl or cycloalkyl group. The term“heteroalkoxy” similarly means a group having the structure —OR, where Ris a heteroalkyl or heterocyclyl. Alkoxy is optionally substituted.

The terms “cycloalkyl” and “heterocyclyl,” by themselves or incombination with other terms, means cyclic versions of “alkyl” and“heteroalkyl”, respectively. Additionally, for heterocyclyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Cycloalkyl or heterocyclyl can besaturated or unsaturated or polyunsaturated.

The term “aryl” means a polyunsaturated hydrocarbon substituent. Arylgroups can be monocyclic or polycyclic (e.g., 2 to 3 rings that arefused together or linked covalently). The term “heteroaryl” refers to anaryl group that contains one to four heteroatoms selected from N, O, andS. A heteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below.

Various groups are described herein as substituted or unsubstituted(i.e., optionally substituted). Optionally substituted groups mayinclude one or more substituents independently selected from: halogen,nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, oxo, carbamoyl,alkyl, heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)₂amino,alkylsulfinyl, alkylsulfonyl, arylsulfonyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. Incertain aspects the optional substituents may be further substitutedwith one or more substituents independently selected from: halogen,nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl(—C(O)NR₂), unsubstituted alkyl, unsubstituted heteroalkyl, alkoxy,alkylthio, alkylamino, (alkyl)₂amino, alkylsulfinyl, alkyl sulfonyl,aryl sulfonyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl,unsubstituted aryl, or unsubstituted heteroaryl. Exemplary optionalsubstituents include, but are not limited to: —OH, oxo (═O), —Cl, —F,Br, C₁₋₄alkyl, phenyl, benzyl, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—NO₂, —S(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), —CO₂(C₁₋₄alkyl), and—O(C₁₋₄alkyl).

The term “pharmaceutically acceptable salts,” as used herein, refers tosalts of compounds of this invention that are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of a compound of this invention with aninorganic or organic acid, or an organic base, depending on thesubstituents present on the compounds of the invention.

Non-limiting examples of inorganic acids which may be used to preparepharmaceutically acceptable salts include: hydrochloric acid, phosphoricacid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acidand the like. Examples of organic acids which may be used to preparepharmaceutically acceptable salts include: aliphatic mono- anddicarboxylic acids, such as oxalic acid, carbonic acid, citric acid,succinic acid, phenyl-heteroatom-substituted alkanoic acids, aliphaticand aromatic sulfuric acids and the like. Pharmaceutically acceptablesalts prepared from inorganic or organic acids thus includehydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate,sulfite, bisulfate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate,p-toluenesulfonate, methanesulfonate, maleate, and the like.

Suitable pharmaceutically acceptable salts may also be formed byreacting the agents of the invention with an organic base such asmethylamine, ethylamine, ethanolamine, lysine, ornithine and the like.Pharmaceutically acceptable salts include the salts formed betweencarboxylate or sulfonate groups found on some of the compounds of thisinvention and inorganic cations, such as sodium, potassium, ammonium, orcalcium, or such organic cations as isopropylammonium,trimethylammonium, tetramethylammonium, and imidazolium.

It should be recognized that the particular anion or cation forming apart of any salt of this invention is not critical, so long as the salt,as a whole, is pharmacologically acceptable.

Additional examples of pharmaceutically acceptable salts and theirmethods of preparation and use are presented in Handbook ofPharmaceutical Salts: Properties, Selection and Use (2002), which isincorporated herein by reference.

An “isomer” of a first compound is a separate compound in which eachmolecule contains the same constituent atoms as the first compound, butwhere the configuration of those atoms in three dimensions differs.Unless otherwise specified, the compounds described herein are meant toencompass their isomers as well. A “stereoisomer” is an isomer in whichthe same atoms are bonded to the same other atoms, but where theconfiguration of those atoms in three dimensions differs. “Enantiomers”are stereoisomers that are mirror images of each other, like left andright hands. “Diastereomers” are stereoisomers that are not enantiomers.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

IV. Examples

The following examples as well as the figures are included todemonstrate preferred embodiments of the invention. It should beappreciated by those of skill in the art that the techniques disclosedin the examples or figures represent techniques discovered by theinventors to function well in the practice of the invention, and thuscan be considered to constitute preferred modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the invention.

EXAMPLE 1(4aR,5S,6S,6aR,9S,11aS,11bS,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylenedecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-1,7(8H)-dione(CYD-5-28)

To a stirring solution of oridonin (500 mg, 1.37 mmol) in acetone (40mL) was added Jones reagent (0.6 mL) dropwise at ice-water bath. Theresulting mixture was stirred at 0° C. for 20 min, and isopropanol wasadded to quench excess Jones reagent. Then the mixture was diluted withwater and extracted with dichloromethane. The extract was washed withbrine, dried over anhydrous Na₂SO₄, filtered, and evaporated to give asolid crude product. The crude residue was recrystallized fromacetone-hexane to give CYD-5-28 as a white solid (410 mg, 82%); mp219-220° C. (Lit. mp 219-221° C.). ¹H NMR (600 MHz, (CD₃)₂CO): δ 6.52(br s, 1H), 6.10 (s, 1H), 5.62 (s, 1H), 5.41 (d, 1H, J=10.8 Hz), 5.24(s, 1H), 4.91 (s, 1H), 4.22 (d, 1H, J=10.2 Hz), 3.92 (d, 1H, J=10.8 Hz),3.69 (m, 1H), 3.31 (br s, 1H), 3.01 (d, 1H, J=9.6 Hz), 2.76 (m, 5H),2.46 (m, 1H), 2.36 (m, 1H), 2.19 (m, 1H), 1.92 (m, 3H), 1.68 (m, 1H),1.61 (m, 1H), 1.19 (m, 1H), 1.14 (s, 3H), 0.97 (s, 3H).

EXAMPLE 2(4aR,5S,6S,6aR,9S,11aS,11bS,14R)-2-bromo-5,6,14-trihydroxy-4,4-dimethyl-8-methylenedecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-1,7(8H)-dione(CYD-5-38)

To a solution of CYD-5-28 (100 mg, 0.27 mmol) in THF (4 mL) was addedPyHBr₃ (88 mg, 0.27 mmol) at room temperature. The reaction mixture wasstirred at room temperature (rt) for 4 h and then poured into water andextracted with CH₂Cl₂ (30 mL×3). The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to give anoily residue. The residue was purified by silica gel column; elutionwith 50% EtOAc in hexane afforded the desired product CYD-5-38 (80 mg,66%) as a colorless amorphous gel; one isomer: ¹H NMR (600 MHz, CDCl₃):δ 6.26 (s, 1H), 6.09 (d, 1H, J=11.4 Hz), 6.00 (br s, 1H), 5.65 (s, 1H),4.91 (s, 1H), 4.72 (br s, 1H), 4.31 (m, 2H), 3.97 (d, 1H, J=10.8 Hz),3.80 (m, 1H), 3.08 (d, 1H, J=9.0 Hz), 2.59 (dd, 1H, J=4.8 Hz, 13.2 Hz),2.24 (d, 1H, J=8.4 Hz), 2.12 (m, 1H), 1.90 (m, 1H), 1.65 (m, 1H), 1.43(m, 1H), 1.21 (s, 3H), 0.98 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 206.4,202.6, 150.6, 122.3, 98.0, 72.9, 72.2, 65.6, 61.7, 58.1, 52.2, 49.8,48.4, 45.1, 42.7, 33.8, 29.8, 29.4, 22.3, 18.1; another isomer: ¹H NMR(600 MHz, CDCl₃): δ 6.26 (s, 1H), 5.98 (d, 1H, J=12.0 Hz), 6.00 (br s,1H), 5.66 (s, 1H), 4.87 (s, 1H), 4.80 (m, 1H), 4.39 (d, 1H, J=10.8 Hz4),4.06 (d, 1H, J=10.8 Hz), 3.80 (m, 1H), 3.08 (d, 1H, J=9.0 Hz), 2.67 (m,1H), 2.36 (d, 1H, J=5.4 Hz), 2.33 (d, 1H, J=5.4 Hz), 2.12 (m, 1H), 1.90(m, 1H), 1.65 (m, 1H), 1.25 (m, 1H), 1.22 (s, 3H), 1.05 (m, 1H), 1.04(s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 206.2, 202.6, 150.5, 122.6, 98.0,72.9, 71.9, 64.5, 61.2, 58.7, 51.4, 49.8, 48.9, 45.1, 42.6, 34.8, 30.4,29.3, 24.9, 18.9. HRMS calc. for C₂₀H₂₅BrO₆: [M+H]⁺441.0907; found441.0909.

EXAMPLE 3(6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-2,5,5-trimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-5-19)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was addedthioacetamide (12 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 50% EtOAc in hexane afforded thedesired product CYD-6-19 (20 mg, 42%) as an amorphous gel; [α]_(D)²⁵+184 (c 0.1, CHCl₃); HPLC purity 97.6% (t_(R)=12.4 min); ¹HNMR (600MHz, CDCl₃): δ 10.62 (br s, 1H), 6.18 (s, 1H), 5.81 (d, 1H, J=12.6 Hz),5.57 (d, 1H, J=0.6 Hz), 5.24 (br s, 1H), 5.16 (br s, 1H), 4.96 (d, 1H,J=1.2 Hz), 4.72 (s, 1H), 4.36 (dd, 1H, J=0.6 Hz, 10.2 Hz), 4.08 (dd, 1H,J=10.2 Hz), 3.79 (m, 1H), 3.03 (d, 1H, J=9.6 Hz), 2.45 (m, 1H), 2.25 (d,1H, J=15.0 Hz), 2.04 (d, 1H, J=14.4 Hz), 1.99 (m, 2H), 1.92 (s, 3H),1.66 (d, 1H, J=3.6 Hz), 1.59 (m, 2H), 1.21 (s, 3H), 1.00 (s, 3H). ¹³CNMR (150 MHz, CDCl₃): δ 206.7, 192.7, 162.0, 151.6, 121.3, 100.6, 98.1,73.2, 72.0, 66.5, 62.4, 58.4, 51.6, 46.4 (2C), 42.5, 32.9, 30.5, 30.2,21.7, 20.7, 20.1. MS (+ESI-LR): m/z=418.1 [M+H]⁻; HRMS calc. forC₂₂H₂₇NO₅S: [M+H]⁺ 418.1683; found 418.1685.

EXAMPLE 4 (5aR,6S,7S,7aR,10S,12a5,12bR,15R)-2-amino-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-5-41)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was addedthiourea (12 mg, 0.16 mmol) at room temperature. The reaction mixturewas heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 51% EtOAc in hexane afforded thedesired product CYD-5-41 (25 mg, 53%) as an amorphous gel; [α]_(D)²⁵+190 (c 0.1, CHCl₃); HPLC purity 97.0% (t_(R)=9.0 min); ¹H NMR (600MHz, CDCl₃+CD₃OD): δ 6.16 (s, 1H), 5.59 (s, 1H), 5.01 (s, 1H), 4.37 (d,1H, J=10.2), 3.96 (d, 1H, J=9.6 Hz), 3.80 (d, 1H, J=3.0 Hz), 3.32 (s,1H), 3.01 (d, 1H, J=3.6 Hz), 2.52 (m, 2H), 2.31 (d, 1H, J=15.6 Hz), 2.12(m, 1H), 1.94 (dd, 1H, J=4.8 Hz, 13.8 Hz), 1.83 (m, 1H), 1.69 (d, 1H,J=9.0 Hz), 1.58 (m, 1H), 1.25 (s, 3H), 0.99 (s, 3H). ¹³C NMR (150 MHz,CDCl₃+CD₃OD): δ 206.8, 166.0, 151.4, 141.7, 120.4, 120.2, 97.5, 72.7,72.5, 64.9, 61.9, 59.1, 53.1, 43.2, 40.5, 38.6, 34.6, 30.2, 29.8, 20.2,20.1. MS (+ESI-LR): m/z=419.1 [M+H]⁺; HRMS calc. for C₂₁H₂₆N₂O₅S: [M+H]⁺419.1635; found 419.1638.

EXAMPLE 5 (5 aR,6S,7S,7aR,10S,12a5,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-2-(methylamino)-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-5-54)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added1-methylthiourea (14 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 50% EtOAc in hexane afforded thedesired product CYD-5-54 (25 mg, 52%) as an amorphous gel; [α]_(D)²⁵+146 (c 0.1, CHCl₃); HPLC purity 95.6% (t_(R)=15.7 min); ¹H NMR (600MHz, CDCl₃): δ 6.80 (br s, 1H), 6.17 (s, 1H), 5.97 (d, 1H, J=12.0 Hz),5.80 (br s, 1H), 5.56 (s, 1H), 5.03 (br s, 2H), 4.65 (d, 1H, J=10.2 Hz),3.87 (d, 1H, J=10.2 Hz), 3.77 (dd, 1H, J=9.6 Hz, 12.0 Hz), 3.05 (d, 1H,J=9.0 Hz), 2.86 (s, 3H), 2.50 (m, 2H), 2.32 (d, 1H, J=16.2 Hz), 2.15 (m,1H), 2.04 (s, 3H), 1.88 (m, 1H), 1.82 (m, 1H), 1.69 (d, 1H, J=9.0 Hz),1.53 (m, 1H), 1.22 (s, 3H), 0.93 (s, 3H). ¹³C NMR (150 MHz,CDCl₃+CD₃OD): δ 206.7, 168.5, 151.9, 143.1, 120.9, 118.8, 97.9, 73.5,72.1, 65.1, 62.6, 58.0, 53.2, 42.7, 41.2, 39.0, 35.0, 32.3, 30.5, 30.2,20.9, 20.4. MS (+ESI-LR): m/z=433.1 [M+H]⁺; HRMS calc. for C₂₂H₂₈N₂O₅S:[M+H]⁺ 433.1792; found 433.1795.

EXAMPLE 6(6S,7S,7aR,10R,12bR,15R)-2-(cyclohexylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-17-2)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added1-cyclohexylthiourea (25 mg, 0.16 mmol) at room temperature. Thereaction mixture was heated under reflux for 3 h. After cooling, themixture was concentrated in vacuo to give an oily residue. The residuewas purified by silica gel column; elution with 50% EtOAc in hexaneafforded the desired product CYD-6-17-2 (30 mg, 52%) as amorphous gel;[α]_(D) ²⁵+132 (c 0.1, CHCl₃); HPLC purity 98.9% (t_(R)=22.2 min); ¹HNMR (600 MHz, CDCl₃): δ 6.84 (br s, 1H), 6.19 (s, 1H), 5.95 (d, 1H,J=12.0 Hz), 5.74 (br s, 1H), 5.58 (s, 1H), 5.04 (s, 2H), 4.67 (m, 1H),3.89 (d, 1H, J=10.2 Hz), 3.80 (m, 1H), 3.08 (d, 2H, J=9.0 Hz), 2.52 (m,2H), 2.31 (d, 1H, J=9.6 Hz), 2.19 (m, 1H), 2.07 (m, 1H), 2.02 (m, 1H),1.89 (dd, 1H, J=4.8 Hz, 13.8 Hz), 1.80 (m, 2H), 1.71 (d, 1H, J=9.0 Hz),1.65 (d, 1H, J=12.6 Hz), 1.56 (m, 1H), 1.28 (m, 6H), 1.27 (s, 3H), 0.97(s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 206.7, 166.5, 152.0, 142.6, 120.8,118.1, 97.9, 73.5, 72.1, 65.0, 62.6, 58.1, 55.7, 53.3, 42.7, 41.2, 39.1,35.0, 32.9, 30.5, 30.2, 29.6, 25.5, 25.0, 21.0, 20.4. MS (+ESI-LR):m/z=501.2 [M+H]⁺; HRMS calc. for C₂₇H₃₆N₂O₅S: [M+H]⁺ 501.2418; found501.2423.

EXAMPLE 7(5aR,6S,7S,7aR,10S,12aS,12bR,15R)-2-(allylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-18)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added1-allylthiourea (18 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 50% EtOAc in hexane afforded thedesired product CYD-6-18 (20 mg, 38%) as amorphous gel; [α]_(D) ²⁵+85 (c0.1, CHCl₃); HPLC purity 98.5% (t_(R)=11.8 min); ¹H NMR (600 MHz,CDCl₃): δ 6.30 (br s, 1H), 6.17 (s, 1H), 5.98 (d, 1H, J=11.4 Hz), 5.88(m, 1H), 5.67 (br s, 1H), 5.56 (s, 1H), 5.27 (d, 1H, J=16.8 Hz), 5.18(d, 1H, J=9.6 Hz), 5.02 (s, 1H), 4.91 (br s, 1H), 4.57 (d, 1H, J=10.2Hz), 3.91 (d, 1H, J=10.2 Hz), 3.80 (m, 3H), 3.05 (d, 1H, J=9.6 Hz), 2.48(m, 2H), 2.31 (d, 1H, J=15.6 Hz), 2.13 (m, 1H), 1.86 (m, 2H), 1.69 (d,1H, J=9.0 Hz), 1.54 (m, 1H), 1.24 (s, 3H), 0.95 (s, 3H). ¹³C NMR (150MHz, CDCl₃): δ 206.7, 166.7, 151.8, 142.8, 133.7, 121.0, 119.3, 117.2,97.9, 73.5, 72.1, 65.2, 62.6, 58.0, 53.2, 48.4, 42.7, 41.1, 39.0, 35.0,30.5, 30.2, 21.0, 20.4. MS (+ESI-LR): m/z=459.2 [M+H]⁻; HRMS calc. forC₂₄H₃₀N₂O₅S: [M+H]⁺ 459.1948; found 459.1952.

EXAMPLE 8(6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-2-((2-(piperidin-1-yl)ethyl)amino)-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-20)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added1-(2-(piperidin-1-yl)ethyl) thiourea (30 mg, 0.16 mmol) at roomtemperature. The reaction mixture was heated under reflux for 3 h. Aftercooling, the mixture was concentrated in vacuo to give an oily residue.The residue was purified by silica gel column; elution with 5% MeOH inCH₂Cl₂ afforded the desired product CYD-6-20 (31 mg, 51%) as anamorphous gel; [α]_(D) ²⁵+138 (c 0.1, CHCl₃); HPLC purity 98.5%(t_(R)=10.5 min); ¹H NMR (600 MHz, CDCl₃): δ 6.18 (s, 1H), 6.06 (d, 1H,J=12.0 Hz), 5.74 (br s, 1H), 5.57 (s, 1H), 5.03 (s, 1H), 4.47 (d, 1H,J=10.2 Hz), 3.99 (d, 1H, J=10.2 Hz), 3.85 (dd, 1H, J=9.0 Hz, 12.0 Hz),3.26 (t, 2H, J=5.4 Hz), 3.05 (d, 1H, J=9.6 Hz), 2.57 (m, 2H), 2.48 (m,6H), 2.33 (d, 1H, J=15.6 Hz), 2.14 (m, 1H), 1.92 (m, 2H), 1.71 (d, 1H,J=8.4 Hz), 1.59 (m, 5H), 1.46 (m, 2H), 1.27 (s, 3H), 0.99 (s, 3H). ¹³CNMR (150 MHz, CDCl₃): δ 206.7, 166.1, 151.8, 143.0, 120.9, 119.1, 97.8,73.5, 72.2, 65.6, 62.6, 58.1, 57.2, 54.4 (2C), 53.2, 42.8, 42.1, 41.0,39.0, 35.0, 30.5, 30.3, 25.6 (2C), 24.2, 21.0, 20.3. MS (+ESI-LR):m/z=530.2 [M+H]⁺; HRMS calc. for C₂₈H₃₉N₃O₅S: [M+H]⁺ 530.2683; found530.2687.

EXAMPLE 9N-((6S,7S,7aR,10R,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-8-oxo-5,5a,6,7,8,9,10,11,12,12a-decahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-2-yl)acetamide(CYD-6-21)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was addedacetyl-thiourea (19 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 50% EtOAc in hexane afforded thedesired product CYD-6-21 (19 mg, 36%) as an amorphous gel; [α]_(D) ²⁵+152 (c 0.1, CHCl₃); HPLC purity 99.2% (t_(R)=13.5 min); ¹H NMR (600MHz, CDCl₃): δ 10.29 (s, 1H), 7.96 (br s, 1H), 6.23 (d, 1H, J=12.6 Hz),6.22 (s, 1H), 5.63 (s, 1H), 5.17 (s, 1H), 5.09 (s, 1H), 4.96 (d, 1H,J=10.2 Hz), 3.76 (m, 2H), 3.12 (d, 1H, J=9.6 Hz), 2.56 (m, 2H), 2.45 (d,1H, J=15.6 Hz), 2.30 (s, 3H), 2.24 (m, 1H), 1.93 (dd, 1H, J=3.6 Hz, 13.8Hz), 1.79 (d, 1H, J=9.0 Hz), 1.73 (br s, 1H), 1.57 (m, 2H), 1.26 (s,3H), 0.82 (s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 206.8, 168.9, 156.6,151.5, 140.8, 125.9, 121.7, 98.0, 73.8, 72.0, 64.4, 62.4, 58.1, 52.9,42.6, 41.0, 38.6, 34.9, 30.4, 29.9, 23.0, 20.7, 20.6. MS (+ESI-LR):m/z=461.1 [M+H]⁺; HRMS calc. for C₂₃H₂₈N₂O₆S: [M+H]⁺ 461.1741; found461.1747.

EXAMPLE 10(6S,7S,7aR,10R,12bR,15R)-2-(azepan-1-yl)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-26-2)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was addedazepane-1-carbothioamide (25 mg, 0.16 mmol) at room temperature. Thereaction mixture was heated under reflux for 3 h. After cooling, themixture was concentrated in vacuo to give an oily residue. The residuewas purified by silica gel column; elution with 50% EtOAc in hexaneafforded the desired product CYD-6-26-2 (24 mg, 41%) as an amorphousgel; [α]_(D) ²⁵+148 (c 0.1, CHCl₃); HPLC purity 97.8% (t_(R)=24.3 min);¹H NMR (600 MHz, CDCl₃): δ 6.17 (s, 1H), 6.05 (d, 1H, J=12.0 Hz), 5.56(s, 1H), 5.18 (br s, 1H), 5.01 (d, 1H, J=1.2 Hz), 4.71 (s, 1H), 4.44(dd, 1H, J=1.2 Hz, 10.2 Hz), 4.00 (dd, 1H, J=10.2 Hz), 3.86 (dd, 1H,J=9.0 Hz, 12.0 Hz), 3.49 (m, 2H), 3.39 (m, 2H), 3.04 (d, 1H, J=9.6 Hz),3.48 (m, 2H), 2.32 (d, 1H, J=15.6 Hz), 2.05 (m, 2H), 1.91 (m, 1H), 1.72(m, 6H), 1.55 (m, 5H), 1.25 (s, 3H), 0.99 (s, 3H). ¹³C NMR (150 MHz,CDCl₃): δ 206.7, 166.3, 151.7, 143.3, 121.1, 117.6, 97.8, 73.6, 72.2,65.8, 62.7, 57.6, 53.2, 50.2 (2C), 42.7, 40.9, 38.8, 35.0, 30.4, 29.6,27.9 (2C), 27.7 (2C), 21.1, 20.2. MS (+ESI-LR): m/z=501.2 [M+H]⁻; HRMScalc. for C₂₇H₃₆N₂O₅S: [M+H]⁺ 501.2418; found 501.2422.

EXAMPLE 11(5aR,6S,7S,7aR,10S,12a5,12bR,15R)-2-(butylamino)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-28)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added1-butylthiourea (21 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 50% EtOAc in hexane afforded thedesired product CYD-6-28 (28 mg, 48%) as an amorphous gel; [α]_(D) ²⁵+142 (c 0.1, CHCl₃); HPLC purity 98.0% (t_(R)=13.7 min); ¹H NMR (600MHz, CDCl₃): δ 6.80 (br s, 1H), 6.17 (s, 1H), 5.94 (d, 1H, J=12.0 Hz),5.74 (br s, 1H), 5.56 (s, 1H), 5.02 (s, 1H), 4.64 (d, 1H, J=10.2 Hz),3.88 (d, 1H, J=10.2 Hz), 3.78 (m, 1H), 3.10 (d, 1H, J=4.2 Hz), 3.05 (d,1H, J=9.0 Hz), 2.50 (m, 2H), 2.31 (d, 1H, J=16.2 Hz), 2.15 (m, 1H), 1.88(dd, 1H, J=4.8 Hz, 13.8 Hz), 1.81 (m, 1H), 1.69 (d, 1H, J=9.6 Hz), 1.61(m, 2H), 1.54 (m, 1H), 1.39 (m, 2H), 1.24 (s, 3H), 0.93 (m, 6H). ¹³C NMR(150 MHz, CDCl₃): δ 206.8, 167.6, 151.9, 142.8, 120.9, 118.4, 97.9,73.5, 72.1, 65.1, 62.6, 58.1, 53.3, 46.2, 42.7, 41.2, 39.0, 35.0, 31.3,30.5, 30.2, 20.9, 20.5, 20.1, 13.8. MS (+ESI-LR): m/z=475.2 [M+H]⁺; HRMScalc. for C₂₅H₃₄N₂O₅S: [M+H]⁺ 475.2261; found 475.2264.

EXAMPLE 121-((5aR,6S,7S,7aR,10S,12a5,12bR,15R)-6,7,15-trihydroxy-5,5-dimethyl-9-methylene-8-oxo-5,5a,6,7,8,9,10,11,12,12a-decahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-2-yl)guanidine(CYD-6-29)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was addedamidinothiourea (19 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasacidified with 5% HCl aqueous solution, and concentrated in vacuo togive an oily residue. The residue was purified by silica gel column;elution with 5% MeOH in CH₂Cl₂ afforded the desired product CYD-6-29 (28mg, 50%) as a colorless solid; [α]_(D) ²⁵ +108 (c 0.1, CHCl₃/CH₃OH=4:1);HPLC purity 95.1% (t_(R)=5.7 min); ¹H NMR (600 MHz, CD₃OD+CDCl₃): δ 6.19(s, 1H), 5.62 (s, 1H), 5.06 (s, 1H), 4.44 (d, 1H, J=9.6 Hz), 4.00 (d,1H, J=9.0 Hz), 3.85 (d, 1H, J=8.4 Hz), 3.05 (d, 1H, J=9.0 Hz), 2.66 (d,1H, J=16.2 Hz), 2.55 (m, 2H), 2.24 (m, 1H), 2.09 (dd, 1H, J=4.8 Hz, 13.2Hz), 1.81 (d, 1H, J=8.4 Hz), 1.72 (m, 1H), 1.62 (m, 1H), 1.30 (s, 3H),1.01 (s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 206.7, 156.5, 154.4, 151.1,142.9, 126.6, 120.9, 97.5, 72.5, 64.8, 61.7, 58.8, 52.5, 43.1, 40.2,38.0, 34.7, 30.0, 29.7, 29.3, 20.1, 19.6. MS (+ESI-LR): m/z=461.1[M+H]⁺; HRMS calc. for C₂₂H₂₈N₄O₅S: [M+H]⁺ 461.1853; found 461.1856.

EXAMPLE 13(5aR,6S,7S,7aR,10S,12a5,12bR,15R)-6,7,15-trihydroxy-2-(isopropylamino)-5,5-dimethyl-9-methylene-5,5a,6,7,10,11,12,12a-octahydro-4H-7,12b-(epoxymethano)-7a,10-methanocyclohepta[7,8]naphtho[1,2-d]thiazol-8(9H)-one(CYD-6-30)

To a solution of CYD-5-38 (50 mg, 0.11 mmol) in ethanol (4 mL) was added1-isopropylthiourea (19 mg, 0.16 mmol) at room temperature. The reactionmixture was heated under reflux for 3 h. After cooling, the mixture wasconcentrated in vacuo to give an oily residue. The residue was purifiedby silica gel column; elution with 50% EtOAc in hexane afforded thedesired product CYD-6-30 (23 mg, 44%) as amorphous gel; [α]_(D) ²⁵ +161(c 0.1, CHCl₃); HPLC purity 98.0% (t_(R)=12.3 min); ¹H NMR (600 MHz,CDCl₃): δ 6.64 (br s, 1H), 6.17 (s, 1H), 5.93 (d, 1H, J=12.6 Hz), 5.56(s, 2H), 5.02 (s, 2H), 4.64 (d, 1H, J=10.2 Hz), 3.89 (d, 1H, J=10.2 Hz),3.79 (dd, 1H, J=9.6 Hz), 3.47 (m, 1H), 3.06 (d, 1H, J=9.6 Hz), 2.50 (m,2H), 2.30 (d, 1H, J=16.2 Hz), 2.15 (m, 1H), 1.88 (m, 1H), 1.83 (m, 1H),1.69 (d, 1H, J=9.6 Hz), 1.53 (m, 1H), 1.25 (s, 3H), 1.24 (s, 3H), 1.23(s, 3H), 0.95 (s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 206.7, 166.3, 151.9,142.6, 120.9, 118.4, 97.9, 73.5, 72.1, 65.1, 62.6, 58.0, 53.3, 48.2,42.7, 41.2, 39.0, 35.0, 30.6, 30.2, 22.8, 22.6, 21.0, 20.5. MS(+ESI-LR): m/z=461.2 [M+H]⁺; HRMS calc. for C₂₄H₃₂N₂O₅S: [M+H]⁺461.2105; found 461.2111.

EXAMPLE 14(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-3,3a,7,7a,8,11b-hexahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-11,14(2H)-dione (CYD-6-25)

To a solution of CYD-5-38 (80 mg, 0.18 mmol) in acetone (4 mL) was addedTsOH (5 mg) and 2,2-dimethoxypropane (0.32 mL) at rt. The resultingmixture was stirred at rt for 2 hrs. After that, the reaction mixturewas diluted with water and extracted with dichloromethane. The extractwas washed with saturated NaHCO₃ solution and brine, dried overanhydrous Na₂SO₄, filtered, and evaporated to afford compound CYD-5-43(83 mg, 95%) as a colorless gel. To a solution of CYD-5-43 (50 mg, 0.10mmol) in toluene (5 mL) was added DBU (20 mg, 0.13 mmol) at rt. Theresulting mixture was stirred at 110° C. for 4 hrs, and diluted withwater and extracted with EtOAc. The organic extract was washed with 3 NHCl aqueous solution and brine, dried over anhydrous Na₂SO₄, filtered,and evaporated to give an oily residue, which was purified usingpreparative TLC developed by 30% EtOAc in hexane to afford the desiredproduct CYD-6-25 as a colorless amorphous gel (30 mg, 72%). HPLC purity98.7% (t_(R)=19.78 min). ¹H NMR (600 MHz, CDCl₃) δ 6.80 (d, 1H, J=9.6Hz), 6.17 (s, 1H), 5.84 (d, 1H, J=10.2 Hz), 5.59 (s, 1H), 5.41 (d, 1H,J=12.0 Hz), 4.88 (s, 1H), 4.24 (dd, 1H, J=1.2 Hz, 10.2 Hz), 4.08 (m,2H), 3.08 (d, 1H, J=9.0 Hz), 2.53 (m, 1H), 2.00 (m, 3H), 1.67 (s, 3H),1.62 (m, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.27 (s, 3H). ¹³C NMR (150MHz, CDCl₃) δ 204.7, 196.5, 162.1, 150.4, 126.6, 120.8, 101.3, 95.7,71.7, 69.9, 65.1, 56.5, 55.9, 47.4, 45.8, 40.1, 35.9, 30.4, 30.2, 30.1,25.4, 25.0, 19.3. HRMS Calcd for C₂₃H₂₉O₆: [M+H]⁺ 401.1959; found401.1957.

EXAMPLE 15(4aR,5S,6S,6aR,9S,11aS,11bS,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-1,7(8H)-dione(CYD-6-58)

To a solution of CYD-6-25 (8.0 mg, 0.02 mmol) in a mixture of MeOH (2mL) and CH₂Cl₂ (0.5 mL) was added 5% HCl aqueous solution (0.5 mL) atrt. The resulting mixture was stirred at rt for 4 hrs. After that, thereaction mixture was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 50% EtOAc in hexane to afford the desiredproduct CYD-6-58 as a colorless amorphous gel (5.0 mg, 69%). HPLC purity99.0% (t_(R)=16.02 min). ¹H NMR (600 MHz, CDCl₃+CD₃OD) δ 6.88 (d, 1H,J=9.6 Hz), 6.21 (s, 1H), 5.87 (d, 1H, J=10.2 Hz), 5.63 (s, 1H), 4.97 (s,1H), 4.27 (m, 2H), 4.06 (dd, 1H, J=1.2 Hz, 10.2 Hz), 3.96 (d, 1H, J=8.4Hz), 3.04 (d, 1H, J=9.6 Hz), 2.52 (m, 1H), 2.10 (m, 2H), 2.03 (d, 1H,J=8.4 Hz), 1.62 (m, 1H), 1.48 (m, 1H), 1.39 (s, 3H), 1.27 (s, 3H). ¹³CNMR (150 MHz, CDCl₃+CD₃OD) δ 206.7, 197.3, 161.8, 150.8, 126.8, 121.2,97.9, 72.3, 72.2, 65.2, 61.4, 56.8, 50.0, 45.9, 42.7, 35.7, 29.8, 29.4,23.9, 18.9; HRMS Calcd for C₂₀H₂₅O₆: [M+H]⁺ 361.1646; found 361.1544.

EXAMPLE 16 (3S,3aR,3a¹R,6aR,7S,7aR,11S,11aS,11bS)-7-hydroxy-5, 5,8,8-tetramethyl-15-methylene-14-oxodecahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-11-ylmethanesulfonate (CYD-5-61)

To a solution of oridonin (500 mg, 1.36 mmol) in acetone (20 mL) wasadded TsOH (20 mg) and 2,2-dimethoxypropane (3.0 mL) at rt. Theresulting mixture was stirred at rt for 2 hrs. After that, the reactionmixture was diluted with water and extracted with dichloromethane. Theextract was washed with saturated NaHCO₃ (aq.) solution and brine, driedover anhydrous Na₂SO₄, filtered, and evaporated to afford compoundCYD-5-60 as a colorless gel (520 mg, 93%). To a solution of CYD-5-60(277 mg, 0.68 mmol) in dichloromethane was added Et₃N (138 mg, 1.37mmol) and MsCl (94 mg, 0.82 mmol) slowly at 0° C. The mixture wasstirred at rt overnight, and diluted with water and extracted withdichloromethane. The organic extract was washed with saturated NaHCO₃(aq.) solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The crude residue was furtherpurified by silica gel column; elution with 50% EtOAc in hexane affordedthe desired product CYD-5-61 as a colorless gel (264 mg, 80%). ¹H NMR(600 MHz, CDCl₃) δ 6.16 (s, 1H), 5.82 (d, 1H, J=12.0 Hz), 5.58 (s, 1H),4.76 (dd, 1H, J=6.0 Hz, 12.0 Hz), 4.14 (d, 1H, J=4.2 Hz), 3.92 (m, 1H),3.07 (d, 1H, J=9.0 Hz), 2.99 (s, 3H), 2.51 (m, 1H), 2.05 (m, 1H), 1.89(m, 2H), 1.77 (m, 3H), 1.63 (s, 3H), 1.52 (m, 1H), 1.38 (d, 1H, J=7.2Hz), 1.33 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H), 1.16 (d, 1H, J=7.2 Hz).¹³C NMR (150 MHz, CDCl₃) δ 205.1, 150.4, 120.5, 101.0, 94.6, 84.7, 72.9,69.9, 62.3, 59.5, 55.9, 50.0, 40.6, 40.1, 38.2, 33.2, 33.0, 31.5, 30.1(2C), 26.4, 25.4, 22.4, 18.8; HRMS Calcd for C₂₄H₃₅O₈S: [M+H]⁺ 483.2047;found 483.2052.

EXAMPLE 17(3S,3aR,3a¹R,6aR,7S,7aR,11aR,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-2,3,3a,7,7a,8,9,11b-octahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-6-75)

To a solution of CYD-5-61 (34 mg, 0.07 mmol) in DMF (5 mL) was addedLiBr (18 mg, 0.21 mmol) and Li₂CO₃ (15 mg, 0.21 mmol) at rt. Theresulting mixture was stirred at 115° C. for 2 hrs. After that, thereaction mixture was diluted with water and extracted with EtOAc. Theorganic extract was washed with saturated NaHCO₃ (aq.) solution andbrine, dried over anhydrous Na₂SO₄, filtered, and evaporated to give anoily residue. The crude residue was further purified by silica gelcolumn; elution with 25% EtOAc in hexane afforded the desired productCYD-5-75 as a colorless gel (25 mg, 84%). HPLC purity 99.8% (t_(R)=18.30min). ¹H NMR (600 MHz, CDCl₃) δ 6.16 (s, 1H), 5.77 (m, 1H), 5.56 (s,1H), 5.41 (d, 1H, J=12.0 Hz), 5.19 (dd, 1H, J=3.0 Hz, 10.2 Hz), 4.82 (s,1H), 3.99 (d, 1H, J=10.2 Hz), 3.90 (dd, 1H, J=8.4 Hz, 12.0 Hz), 3.81 (d,1H, J=9.6 Hz), 3.06 (d, 1H, J=9.0 Hz), 2.53 (m, 1H), 1.95 (d, 1H, J=17.4Hz), 1.76 (m, 4H), 1.65 (s, 3H), 1.56 (m, 1H), 1.50 (d, 1H, J=8.4 Hz),1.35 (s, 3H), 1.18 (s, 3H), 1.05 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ204.5, 150.5, 130.3, 124.1, 120.4, 101.2, 95.4, 72.0, 70.1, 64.8, 57.9,56.3, 49.1, 41.1, 40.3, 38.1, 32.2, 31.1, 30.3, 30.1, 25.5, 22.1, 17.3.HRMS Calcd for C₂₃H₃₁O₅: [M+H]⁺ 387.2166; found 387.2169.

EXAMPLE 18(4aR,5S,6S,6aR,9S,11aS,11bR,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one(CYD-6-82)

To a solution of CYD-6-75 (9.0 mg, 0.02 mmol) in a mixture of MeOH (2mL) and CH₂Cl₂ (0.5 mL) was added 5% HCl aqueous solution (0.5 mL) atrt. The resulting mixture was stirred at rt for 4 hrs. After that, thereaction mixture was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 50% EtOAc in hexane to give the desiredproduct CYD-6-82 as a colorless gel (6.0 mg, 75%). HPLC purity 98.5%(t_(R)=18.30 min). ¹H NMR (600 MHz, CDCl₃) δ 6.22 (s, 1H), 6.01 (d, 1H,J=12.0 Hz), 5.81 (m, 1H), 5.61 (s, 1H), 5.23 (dd, 1H, J=3.0 Hz, 10.2Hz), 4.92 (s, 1H), 4.03 (d, 1H, J=10.2 Hz), 3.85 (m, 2H), 3.08 (d, 1H,J=9.0 Hz), 2.51 (m, 1H), 1.97 (d, 1H, J=18.0 Hz), 1.85 (m, 3H), 1.68 (m,1H), 1.59 (m, 1H), 1.54 (d, 1H, J=9.0 Hz), 1.18 (s, 3H), 1.07 (s, 3H).¹³C NMR (150 MHz, CDCl₃) δ 206.3, 151.3, 130.6, 124.4, 121.3, 97.7,73.6, 72.0, 65.5, 62.2, 57.3, 52.2, 42.5, 40.9, 38.6, 32.3, 30.7, 29.8,21.7, 17.6; HRMS Calcd for C₂₀H₂₇O₅: [M+H]⁺ 347.1853; found 347.1857.

EXAMPLE 19(3S,3aR,3a¹R,6aR,7S,7aS,9S,11aR,11bS)-7,9-dihydroxy-5,5,8,8-tetramethyl-15-methylene-2,3,3a,7,7a,8,9,11b-octahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-6-81)

A mixture of CYD-6-75 (20 mg, 0.05 mmol) and SeO₂ (16 mg, 0.15 mmol) in1,4-dioxane (4 mL) was stirred at 100° C. for 16 hrs. After that, thereaction mixture was filtered, and the filtrate was diluted with waterand extracted with dichloromethane. The extract was washed with brine,dried over anhydrous Na₂SO₄, filtered, and evaporated to give an oilyresidue. The residue was purified using preparative TLC developed by 50%EtOAc in hexane to afford the desired product CYD-6-81 as a colorlessgel (16 mg, 76%). HPLC purity 99.7% (t_(R)=17.31 min). ¹H NMR (600 MHz,CDCl₃) δ 6.16 (s, 1H), 6.00 (dd, 1H, J=6.0 Hz, 10.2 Hz), 5.56 (s, 1H),5.42 (m, 2H), 4.82 (s, 1H), 3.94 (m, 2H), 3.84 (d, 1H, J=9.6 Hz), 3.06(d, 1H, J=9.6 Hz), 2.53 (m, 1H), 1.87 (d, 1H, J=9.0 Hz), 1.82 (m, 2H),1.71 (m, 2H), 1.65 (s, 3H), 1.57 (m, 1H), 1.35 (s, 1H), 1.24 (s, 3H),1.01 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 204.1, 150.3, 130.9, 128.6,120.6, 101.2, 95.5, 72.6, 71.5, 70.0, 64.5, 56.1, 51.0, 48.8, 40.3,38.2, 36.7, 30.2, 30.1, 25.9, 25.4, 21.9, 17.3. HRMS Calcd for C₂₃H₃₁O₆:[M+H]⁺ 403.2115; found 403.2118.

EXAMPLE 20(3S,4aS,5S,6S,6aR,9S,11aS,11bR,14R)-3,5,6,14-tetrahydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one(CYD-6-90)

To a solution of CYD-6-81 (10 mg, 0.025 mmol) in a mixture of MeOH (2mL) and CH₂Cl₂ (0.5 mL) was added 5% HCl aqueous solution (0.5 mL) atrt. The resulting mixture was stirred at rt for 4 hrs. After that, thereaction mixture was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was further purifiedusing preparative TLC developed by 66% EtOAc in hexane to afford thedesired product CYD-6-90 as a colorless gel (8.0 mg, 88%). HPLC purity98.6% (t_(R)=13.17 min). ¹H NMR (600 MHz, CDCl₃) δ 6.19 (s, 1H), 6.02(dd, 1H, J=6.0 Hz, 10.2 Hz), 5.99 (d, 1H, J=12.0 Hz), 5.58 (s, 1H), 5.42(d, 1H, J=10.2 Hz), 5.25 (br s, 1H), 4.89 (s, 1H), 4.61 (s, 1H), 3.96(d, 1H, J=9.6 Hz), 3.85 (m, 2H), 3.65 (d, 1H, J=6.0 Hz), 3.05 (d, 1H,J=9.0 Hz), 2.48 (m, 1H), 1.90 (d, 1H, J=9.0 Hz), 1.84 (m, 2H), 1.67 (m,2H), 1.55 (m, 1H), 1.21 (s, 3H), 1.00 (s, 3H). ¹³C NMR (150 MHz, CDCl₃)δ 206.0, 151.0, 131.2, 128.8, 121.6, 97.8, 73.1, 72.3, 72.0, 65.3, 62.0,51.9, 50.5, 42.5, 38.7, 36.7, 29.7, 25.6, 21.6, 17.6; HRMS Calcd forC₂₀H₂₇O₆: [M+H]⁺ 363.1802; found 363.1803.

EXAMPLE 21(3S,3aR,3a¹R,6aR,7S,7aS,11aR,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-3,3a,7,7a,8,11b-hexahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-9,14(2H)-dione(CYD-6-86)

To a solution if CYD-6-81 (10 mg, 0.025 mmol) in dichloromethane (2 mL)was added PDC (11.2 mg, 0.03 mmol) at rt. The resulting mixture wasstirred at rt for 4 hrs. After that, the reaction mixture was filtered,and the filtrate was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 50% EtOAc in hexane to afford the desiredproduct CYD-6-86 as a colorless gel (9.0 mg, 90%). HPLC purity 97.5%(t_(R)=18.62 min). ¹H NMR (600 MHz, CDCl₃) δ 6.29 (d, 1H, J=10.2 Hz),6.19 (s, 1H), 6.00 (d, 1H, J=10.2 Hz), 5.60 (s, 1H), 5.54 (d, 1H, J=12.0Hz), 4.84 (s, 1H), 4.16 (d, 1H, J=10.2 Hz), 4.07 (m, 1H), 4.01 (d, 1H,J=10.2 Hz), 3.10 (d, 1H, J=8.4 Hz), 2.58 (m, 1H), 1.93 (d, 1H, J=7.8Hz), 1.88 (m, 2H), 1.76 (m, 1H), 1.66 (s, 3H), 1.60 (m, 2H), 1.37 (s,3H), 1.36 (s, 3H), 1.27 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 204.1,203.2, 149.9, 142.6, 129.8, 121.2, 101.5, 95.4, 70.9, 69.8, 64.1, 56.2,55.7, 48.3, 44.6, 40.1, 38.8, 30.1, 29.9, 25.4, 23.9, 22.4, 17.1. HRMSCalcd for C₂₃H₂₉O₆: [M+H]⁺ 401.1959; found 361.1962.

EXAMPLE 22(4aS,5S,6S,6aR,9S,11aS,11bR,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-4,4a,5,6,9,10,11,11a-octahydro-3H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-3,7(8H)-dione(CYD-6-93)

To a solution of CYD-6-86 (15 mg, 0.037 mmol) in a mixture of MeOH (2mL) and CH₂Cl₂ (0.5 mL) was added 5% HCl aqueous solution (0.5 mL) atrt. The resulting mixture was stirred at rt for 4 hrs. After that, thereaction mixture was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 66% EtOAc in hexane to afford the desiredproduct CYD-6-93 as a colorless gel (10 mg, 74%). HPLC purity 98.2%(t_(R)=14.87 min). ¹H NMR (600 MHz, CDCl₃) δ 6.31 (d, 1H, J=10.2 Hz),6.22 (s, 1H), 6.13 (d, 1H, J=11.4 Hz), 6.02 (d, 1H, J=10.8 Hz), 5.63 (s,1H), 4.92 (s, 1H), 4.17 (d, 1H, J=10.2 Hz), 4.06 (dd, 1H, J=1.8 Hz, 10.2Hz), 3.98 (m, 1H), 3.10 (d, 1H, J=9.0 Hz), 2.58 (m, 1H), 1.95 (d, 1H,J=9.0 Hz), 1.91 (m, 2H), 1.65 (m, 3H), 1.34 (s, 3H), 1.26 (s, 3H). ¹³CNMR (150 MHz, CDCl₃) δ 206.0, 202.8, 150.5, 142.7, 130.0, 122.2, 97.7,72.4, 72.1, 64.8, 61.7, 55.6, 51.4, 44.4, 42.5, 39.2, 29.4, 23.6, 22.0,17.5; HRMS Calcd for C₂₀H₂₅O₆: [M+H]⁺ 361.1646; found 361.1651.

EXAMPLE 23(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS,Z)-10-((dimethylamino)methylene)-7-hydroxy-5,5,8,8-tetramethyl-15-methyleneoctahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-11,14(2H)-dione(CYD-6-77)

To a solution of CYD-5-28 (250 mg, 0.68 mmol) in acetone (10 mL) wasadded TsOH (20 mg) and 2,2-dimethoxypropane (1.0 mL) at rt. Theresulting mixture was stirred at rt for 2 hrs. After that, the reactionmixture was diluted with water and extracted with dichloromethane. Theextract was washed with saturated NaHCO₃ (aq.) solution and brine, driedover anhydrous Na₂SO₄, filtered, and evaporated to afford compoundCYD-5-29 as a colorless gel (230 mg, 83%). To a solution of CYD-5-29(230 mg, 0.57 mmol) in DMF (4 mL) was added DMF-DMA (136 mg, 1.14 mmol)at rt. The resulting mixture was refluxed at 110° C. for 36 hrs. Afterthat, the solvent was removed under vacuum to give a brown oily residue,which was further purified using preparative TLC developed by 66% EtOAcin hexane to afford the desired product CYD-6-77 as a colorless gel (120mg, 46%). ¹H NMR (600 MHz, CDCl₃) δ 7.42 (s, 1H), 6.14 (s, 1H), 5.55 (s,1H), 5.20 (d, 1H, J=12.0 Hz), 4.87 (s, 1H), 4.31 (d, 1H, J=10.2 Hz),4.04 (d, 1H, J=10.2 Hz), 3.87 (m, 1H), 3.07 (s, 6H), 3.04 (d, 1H, J=9.6Hz), 2.47 (m, 3H), 1.97 (m, 2H), 1.66 (s, 3H), 1.62 (m, 1H), 1.56 (m,2H), 1.34 (s, 3H), 1.23 (s, 3H), 1.00 (s, 3H); HRMS Calcd for C₂₆H₃₆NO₆:[M+H]⁺ 458.2537; found 458.2541.

EXAMPLE 24(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS,Z)-7-hydroxy-10-(hydroxymethylene)-5,5,8,8-tetramethyl-15-methyleneoctahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-11,14(2H)-dione(CYD-6-91)

To a solution of CYD-6-77 (200 mg, 0.43 mmol) in THF (5 mL) was added 2N HCl aqueous solution (0.5 mL) at rt. The resulting mixture was stirredat rt for 1 h. After that, the reaction mixture was diluted with waterand extracted with dichloromethane. The extract was washed withsaturated NaHCO₃ (aq.) solution and brine, dried over anhydrous Na₂SO₄,filtered, and evaporated to give an oily residue. The residue wasfurther purified using preparative TLC developed by 60% EtOAc in hexaneto afford the desired product CYD-6-91 (100 mg, 51%) and the furtherdeprotected product CYD-6-84 (30 mg, 17%) as a colorless gel,respectively.

To a solution of CYD-6-84 (30 mg, 0.076 mmol) in acetone (4 mL) wasadded TsOH (5 mg) and 2,2-dimethoxypropane (0.3 mL) at rt. The resultingmixture was stirred at rt for 2 hrs. After that, the reaction mixturewas diluted with water and extracted with dichloromethane. The extractwas washed with saturated NaHCO₃ (aq.) solution and brine, dried overanhydrous Na₂SO₄, filtered, and evaporated to afford compound CYD-6-91(28 mg, 84%) as a colorless gel.

CYD-6-84: ¹H NMR (300 MHz, CDCl₃) δ 8.33 (s, 1H), 6.21 (s, 1H), 5.83 (d,1H, J=12.0 Hz), 5.61 (s, 1H), 4.96 (s, 1H), 4.33 (d, 1H, J=9.9 Hz), 4.08(d, 1H, J=9.9 Hz), 3.80 (m, 2H), 3.06 (d, 1H, J=9.3 Hz), 2.49 (m, 1H),2.31 (m, 1H), 2.24 (m, 1H), 2.04 (m, 3H), 1.76 (m, 1H), 1.61 (m, 2H),1.25 (s, 3H), 1.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 206.3, 185.8,184.1, 151.1, 121.8, 109.5, 98.0, 72.9, 71.9, 65.1, 62.1, 57.6, 51.3,44.5, 42.4, 39.9, 33.3, 30.1, 29.9, 20.2, 19.9.

CYD-6-91: ¹H NMR (300 MHz, CDCl₃) δ 14.72 (d, 1H, J=3.3 Hz), 8.39 (s,1H), 6.19 (s, 1H), 5.60 (s, 1H), 5.29 (d, 1H, J=12.0 Hz), 4.90 (s, 1H),4.30 (dd, 1H, J=1.2 Hz, 9.9 Hz), 4.09 (dd, 1H, J=0.9 Hz, 9.9 Hz), 3.92(m, 1H), 3.09 (d, 1H, J=9.6 Hz), 2.55 (m, 1H), 2.29 (d, 1H, J=15.0 Hz),2.05 (m, 3H), 1.84 (m, 1H), 1.67 (s, 3H), 1.60 (m, 2H), 1.37 (s, 3H),1.29 (s, 3H), 1.04 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.6, 185.4,184.8, 150.4, 120.7, 109.2, 101.2, 95.7, 71.6, 70.0, 64.4, 58.1, 56.0,48.3, 43.7, 40.1, 39.9, 33.2, 30.5, 30.3, 30.0, 25.3, 20.6, 19.8; HRMSCalcd for C₂₄H₃₁O₇: [M +H]⁺ 431.2064; found 431.2063.

EXAMPLE 25(3S,3aR,3a¹R,6aR,7S,7aR,11aS,11bS)-7-hydroxy-5,5,8,8-tetramethyl-15-methylene-11,14-dioxo-2,3,3a,7,7a,8,11,11b-octahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxine-10-carbaldehyde(CYD-6-92)

To a stirring solution of phenylselenyl chloride (33.6 mg, 0.175 mmol)in CH₂Cl₂ (3 mL) at 0° C. was added pyridine (0.017 mL, 0.208 mmol). Thesolution was stirred for 45 min, and then a solution of a-keto aldehydeCYD-6-91 (60 mg, 0.139 mmol) in CH₂Cl₂ (2 mL) was added. The mixture wasstirred for 15 min at 0° C. and 45 min at rt. It was then extractedtwice with 1 N HCl (aq.). The organic phase was dried over MgSO₄,filtered, and concentrated under reduced pressure. The crude product wasfurther purified using the preparative TLC developed by hexane/EtOAc(1:1) to afford the selenide as yellow gel (60.0 mg, 74%).

To a stirring solution of the above selenide (60.0 mg, 0.102 mmol) inCH₂Cl₂ (5.8 mL) was added 35% H₂O₂ (aq.) solution (0.10 mL, 1.2 mmol).The mixture was vigorously stirred for 5 min, followed by the additionof another portion of 35% H₂O₂ (aq.) solution (0.10 mL, 1.2 mmol) withvigorous stirring for another 5 min. The reaction mixture was thenextracted twice with water. The extract was dried over MgSO₄, filtered,and concentrated under reduced pressure. HPLC purity 98.1% (t_(R)=18.33min). ¹H NMR (600 MHz, CDCl₃) δ 9.83 (s, 1H), 7.59 (s, 1H), 6.18 (s,1H), 5.61 (s, 1H), 5.42 (d, 1H, J=12.6 Hz), 4.89 (s, 1H), 4.33 (dd, 1H,J=1.2 Hz, 10.2 Hz), 4.09 (m, 2H), 3.10 (d, 1H, J=9.0 Hz), 2.56 (m, 1H),2.06 (m, 2H), 2.00 (d, 1H, J=8.4 Hz), 1.67 (s, 3H), 1.56 (m, 3H), 1.52(s, 3H), 1.36 (s, 3H), 1.32 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 204.5,195.2, 188.0, 168.4, 150.0, 133.0, 121.3, 101.5, 95.8, 71.3, 69.8, 64.9,56.1, 55.7, 47.0, 46.5, 40.0, 36.2, 30.0, 29.7, 25.3, 24.2, 19.0. HRMSCalcd for C₂₄H₂₉O₇: [M+H]⁺ 429.1908; found 429.1897.

EXAMPLE 26(2R,4aR,5S,6S,6aR,6a′R,7′S,8′S,8a′R,9S,11aS,11bS,11′S,13a′S,13b′S,14R,16′R)-5,6,7′,8′,14,16′-hexahydroxy-4,4,6′,6′-tetramethyl-8,10′-dimethylene-4,4a,5,6,6′,6a′,7′,8′,9,10,11,11a,11′,12′,13′,13a′-hexadecahydro-3′H-spiro[6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene-2,2′-8,13b-(epoxymethano)-8a,11-methanocyclohepta[3,4]benzo[1,2-h]chromene]-1,7,9′(3H,4′H,5′H,8H,10′H)-trione(CYD-5-40-2)

A mixture of CYD-5-28 (100 mg, 0.138 mmol), dimethylammonium chloride(48 mg, 0.294 mmol), paraformaldehyde (17 mg) in 1,4-dioxane (5 mL) wasstirred and refluxed for 36 hrs. After that, the reaction mixture wasdiluted with water and extracted with dichloromethane. The extract waswashed with saturated NaHCO₃ (aq.) solution and brine, dried overanhydrous Na₂SO₄, filtered, and evaporated to give an oily residue. Theresidue was further purified using preparative TLC developed by 60%EtOAc in hexane to afford the desired product CYD-5-40-1 (23 mg, 22%)and a by-product CYD-5-40-2 (40 mg, 38%) as a colorless solid,respectively. CYD-5-40-1 is not very stable. CYD-5-40-2: HPLC purity99.2% (t_(R)=18.10 min). ¹H NMR (600 MHz, CDCl₃) δ 6.48 (s, 1H), 6.17(s, 1H), 5.81 (s, 1H), 5.58 (s, 1H), 4.89 (s, 1H), 4.71 (s, 1H), 4.37(d, 1H, J=10.2 Hz), 4.00 (m, 3H), 3.79 (d, 1H, J=8.4 Hz), 3.75 (d, 1H,J=8.4 Hz), 3.10 (d, 1H, J=9.0 Hz), 2.95 (d, 1H, J=9.6 Hz), 2.61 (m, 1H),2.55 (m, 1H), 2.30 (m, 2H), 2.08 (m, 2H), 1.94 (m, 3H), 1.84 (m, 1H),1.66 (m, 3H), 1.55 (m, 5H), 1.47 (m, 1H), 1.15 (s, 3H), 1.14 (s, 3H),1.04 (s, 3H), 0.95 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 207.3, 206.8,206.6, 151.6, 151.4, 142.0, 122.5, 121.6, 112.4, 98.4, 98.1, 80.4, 73.2,72.7, 72.5, 65.7, 64.7, 62.3, 61.4, 60.6, 57.5, 53.8, 45.9, 43.4, 43.0,42.0, 33.2, 32.3, 31.5, 30.8, 30.4, 30.0, 29.0, 25.2, 23.3, 20.9, 18.6.HRMS Calcd for C₄₂H₅₃O₁₂: [M H]⁺ 749.3532; found 749.3540.

EXAMPLE 27(2R,4aR,4a′R,5′S,6aR,6′S,6a′R,7S,8S,8aR,9′S,11S,11a′S,11b′S,13aS,13bS,13cR,14′R,17R)-5′,6′,7,8,14′,17-hexahydroxy-4′,4′,6,6-tetramethyl-8′,10-dimethylenehexadecahydro-3H-spiro[4a,13c-epoxy-8,13b-(epoxymethano)-8a,11-methanocyclohepta[3,4]benzo[1,2-h]chromene-2,2′-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalene]-1′,7′,9(3′H,4H,5H,8′H,10H)-trione(CYD-6-39)

To solution of CYD-5-40-2 (15 mg, 0.02 mmol) in dichloromethane (4 mL)was added m-CPBA (4.0 mg, 0.02 mmol) at 0° C. The resulting mixture wasstirred at rt for 1 h. After that, the reaction mixture was diluted withwater and extracted with dichloromethane. The extract was washed withsaturated NaHCO₃ (aq.) solution and brine, dried over anhydrous Na₂SO₄,filtered, and evaporated to give an oily residue. The residue wasfurther purified using preparative TLC developed by 60% EtOAc in hexaneto afford the desired product CYD-6-39 as a colorless solid (12 mg,80%). Its chemical structure and absolute configurations were determinedby X-ray analysis of CYD-6-39 single crystal. HPLC purity 98.7%(t_(R)=15.84 min. ¹H NMR (600 MHz, CDCl₃) δ 6.49 (s, 1H), 6.18 (s, 1H),5.82 (s, 1H), 5.59 (s, 1H), 4.89 (s, 1H), 4.80 (s, 1H), 4.35 (d, 1H,J=10.2 Hz), 4.31 (s, 1H), 4.21 (d, 1H, J=9.6 Hz), 4.15 (d, 1H, J=10.2Hz), 3.99 (d, 1H, J=10.2 Hz), 3.74 (s, 1H), 3.72 (s, 1H), 3.12 (d, 1H,J=9.0 Hz), 2.95 (d, 1H, J=9.6 Hz), 2.63 (m, 1H), 2.51 (m, 1H), 2.46 (d,1H, J=7.8 Hz), 2.37 (m, 1H), 2.19 (m, 1H), 2.11 (m, 1H), 2.01 (d, 1H,J=15.0 Hz), 1.89 (m, 3H), 1.72 (t, 2H, J=13.8 Hz), 1.58 (m, 5H), 1.22(s, 3H), 1.20 (s, 3H), 1.06 (s, 3H), 0.93 (s, 3H). ¹³C NMR (150 MHz,CDCl₃) δ 207.5, 206.1, 151.7, 151.5, 122.2, 121.5, 98.4, 97.7, 86.0,80.5, 73.1, 73.0, 72.9, 72.8, 66.2, 66.0, 64.1, 61.7 (2C), 57.8, 57.4,52.3, 47.0, 43.8, 43.4, 41.9, 33.1, 32.5, 31.1, 30.8, 30.2, 30.0, 29.4,27.3, 25.6, 25.4, 22.5, 19.3, 18.6. HRMS Calcd for C₄₂H₅₃O₁₃: [M+H]⁺765.3481; found 749.3484.

EXAMPLE 28 Retrosynthetic Analysis for the Construction of VariousSubstituted 2H-pyran-Fused Oridonin Derivatives

This synthetic scheme is a retrosynthetic analysis for constructions ofvarious 3,4-dihydro-2H-pyran-fused derivatives of oridonin 1. One step,IED HDA reaction of electron-rich vinyl dienophiles with the exocyclicα,β-unsaturated ketone functionality created in the A-ring would providea direct route to the desired pyran ring. However, two syntheticchallenges arising from this strategy remain to be addressed: (1) How toselectively perform HDA reaction at the A-ring, rather than the enonesystem in the D-ring that is a key bioactivity center; and (2) How toachieve the desired cross-Diels-Alder cycloaddition instead ofhomo-Diels-Alder dimerization from the diversity perspective. Therefore,controlled regio- and stereoselective cross-HDA reactions at the A-ringof oridonin are highly desired.

The synthetic effort commenced with oridonin, a naturally abundant andcommercially available ent-kaurane diterpenoid (Scheme 1). Selectiveoxidation of oridonin with Jones reagent readily provided the 1-ketonederivative CYD-6-58 in 82% yield (Zhou and Cheng, Acta Chim. Sinica1990, 48, 1185-1190). The direct α-methylenation of CYD-6-58 utilizingparaformaldehyde (PFA) and dimethylamine hydrochloride in refluxing1,4-dioxane for 4 h, without any protection, smoothly affordedintermediate 3, in which the exocyclic enone system was successfullyinstalled in the A-ring. However, 3 turned out to be unstable and wasprone to undergo self-dimerization automatically. It was found that thepurified 3 was allowed to stand at −20° C. or rt for 21 days to solelygenerate the spirochroman product 4 in 68% and 72% yield, respectively.When the temperature was increased to 80° C. for 2 days, 4 was obtainedin 80% yield. In a solution of 1,4-dioxane (0.5 mol/L) at rt, thereaction proceeded more slowly than that without solvent; on thecontrary, the reaction was accelerated to give 4 in 70% yield byrefluxing the reaction solution at 110° C. for 4 days. Inspired by thesefindings, we attempted to access 4 directly from CYD-6-58 throughone-pot tandem α-methylenation/homo-HDA reactions. Thus, refluxingCYD-6-58 with PFA and dimethylamine hydrochloride in 1,4-dioxane for 4days readily furnished 4 in 65% yield. The structure of 4 was wellcharacterized by spectroscopic data including ¹H and ¹³C NMR, HRMS, HMQCand HMBC. According to previous reported self-HDA cycloaddition ofα-alkylidene ketones (Li et al. Org. Lett. 2010, 12, 4284-87; Uroos andHayes Org. Lett. 2010, 12, 5294-97; Li et al. J. Am. Chem. Soc. 2012,134, 12414-17), the formation of 4 from 3 is considered to be derivedthrough A-ring-selective HDA reaction between the exocyclic enone of onemolecule and the exomethylene of the other, in which the enoneapproached the exo-methylene from the less hindered a-face, but not theblocked β-face due to the bulky ent-kaurane ring system leading to ahigh facial selectivity. The stereochemistry of the spiro carbon C-2′ of4 was thus tentatively assigned as R configuration, which was furtherconfirmed through X-ray crystallographic analysis at a later stage byconverting 4 into 5. Interestingly, the naturally occurring enone oforidonin was reported to presumably undergo dimerization intobisrubescensin C in vivo (Huang et al. Org. Lett. 2006, 8, 1157-60).Nevertheless, in our cycloaddition reactions, only the enone system inthe A-ring was selectively involved, while the one in the D-ring wasfound intact. The high regioselectivity of this homo-HDA reaction on theenone system is likely ascribed to the less crowded steric environmentof the heterodiene in the A-ring in comparison with that in the D-ring.

EXAMPLE 29 Regio- and Stereoselective Epoxidation of 4 mediated byM-CPBA

Compound 4 was then subjected to an epoxidation reaction by treatmentwith m-CPBA in CH₂Cl₂ at rt, exclusively leading to β-epoxide 5 in agood yield of 80%. The structure of 5 was unambiguously determined byX-ray crystallographic analysis (Scheme 2), which secured thestereochemistry of both 4 and 5. In this step, the reaction occurredpreferentially at the 1-ene rather than two exo-methylenes in the D andD′ rings, respectively, and selectively formed 1,2-epoxide ring from theless sterically hindered β-face. Although some natural ent-kauranedimers isolated from the genus isodon have been previously reported,(Shenet al. Phytochemistry, 1994, 35, 725-29; Na et al. Chin. J. Chem.2002, 20, 884-86; Han et al. Tetrahedron Lett. 2004, 45, 2833-37)homo-dimers 4 and 5 are the first examples of dimeric ent-kauranediterpenoids with the intact enone functionality in the D-ring.

EXAMPLE 30 Cross-HDA Reaction of 7 with N-Butyl Vinyl Ether

While selectively achieving 4 generated excitement, preventing thehomo-dimerization of 3 during the development of A-ring-selectivecross-HDA reactions with the aim to diversely construct pyran-fusedderivatives was one goal. Initially, 3 without any protection was chosenas the heterodiene to undergo Eu(fod)₃-catalyzed cross-HDA reaction withn-butyl vinyl ether at rt for the purpose of atom-economy. The reactionwas very complex with a mixture of several side products includinghomo-dimer 4 as well as partially recovered 3. Accordingly, theacetonide protection of 7,14-dihydroxyl of 3 into 7 was deemed necessaryto avoid potential side reactions. Moreover, introduction of theacetonide protecting group might also enhance the steric effect of theheterodiene in the D-ring leading to an improved regioselectivity forthe A-ring. To reduce the chance of self-dimerization as much aspossible, the protecting group was first installed to form 6 followed byα-methylenation to give the acetonide 7, instead of the directprotecting reaction of 3 (Scheme 3). With 7 in hand, we attempted toinvestigate its cross-HDA reaction with n-butyl vinyl ether. When thereaction was performed in a solution of 1,4-dioxane or THF at rt using10 mol % of Eu(fod)₃ as the catalyst, only trace amount of the desiredcycloadducts 8 and 9 were detected after 72 h; instead, dimer 10 wasobtained in 24% and 21% yields, respectively, together with partiallyrecovered 7. Increasing the reaction temperature to 80° C. predominantlyled to dimer 10 in 62% yield along with cycloadducts 8 and 9 in total15% isolated yield. Both 8 and 9 were fully characterized byspectroscopic data including ¹H and ¹³C NMR, HRMS, HMBC, HMQC and NOESY,respectively, owing to their good separation by preparative TLC.Characteristic HMBC correlations indicate the presence of the pyranmoiety fused into the A-ring of 8 and 9. The stereochemistry of C-2 wasdetermined by NOESY experiments, in which the cross peaks for H-23 andH-1′ of 8 indicated that C-2 had R configuration, and its appendedethereal C—O bond was assigned as α-oriented; on the contrary, nosimilar cross peaks for H-23 and H-1′ of 9 were observed, suggesting C-2had S configuration, and its ethereal C—O bond was on the β-face. Theconformations of the dihydropyran rings in 8 and 9 were also deducedfrom chemical shift values and coupling constants of protons attached toC-2. ¹H NMR spectra of 8 reveal the signals of proton on C-2 as atriplet at 4.89 ppm with a small coupling constant of 2.1 Hz. Thus, theproton at C-2 in 8 is equatorial, while the n-butoxy group occupies theaxial position. For diastereoisomer 9, the proton at C-2 resonates as adoublet of doublets at 4.58 ppm with two coupling constants of 1.5 Hzand 9.0 Hz, respectively, due to coupling with two protons at C-3. Thus,the proton at C-2 in 9 is axial. The stereochemistry of these twoisomers was also secured later by the X-ray crystallographic analysis ofanalogue 20.

Since the undesired homo-dimerization of 7 was still predominant, weattempted to employ n-butyl vinyl ether as solvent to favor the desiredcross-HDA reaction. To our delight, treatment of 7 with 10 mol % ofEu(fod)₃ in a solution of n-butyl vinyl ether for 7 days provided 8 and9 in total 63% yield with the diastereomeric ratio of 53:47 as majorproducts over dimer 10 (18% yield). Moreover, no cycloadducts of theenone in the D-ring were found presumably due to the aforementionedhindered steric effects. In the absence of Eu(fod)₃, no desiredcycloadducts 8 and 9 were observed, suggesting that lanthanide Lewisacid (LA) catalyst is a prerequisite for this HDA reaction due to itsunique properties for coordination to the ketone functionality of theenone system in the A-ring, leading to its activation. Recently,important advances have been made in auxiliary-controlled IED HDAreactions to stereoselectively construct chiral pyran moieties(Pellissier, Tetrahedron 2009, 65, 2839-77; Gizecki et al. Org. Lett.2000, 2, 585-88; Gallier et al. Org. Lett. 2009, 11, 3060-63; Messeretal. J. Org. Chem. 2004, 69, 8558-60; Johnson et al. Chem. Commun. 1998,1019-20). 7 with a stereochemistry-rich framework could be considered asa chiral auxiliary heterodiene, but the stereoselectivity in our casewas very poor. Therefore, we continued our effort to optimize thereaction conditions by screening other Lewis acids and hydrogen bonddonor catalysts. It was found that 10 mol % of Yb(fod)₃ at 32° C.offered an optimal result leading to 8 and 9 in total 68% yield with anenhanced diastereomeric ratio of 10:90. Although their endo/exoselectivity can not be exactly determined due to the structural natureof these substrates, such IED HDA reactions catalyzed by Eu(fod)₃ orYb(fod)₃ are likely endo-selective according to the relevant literature(Gizecki et al. Org. Lett. 2000, 2, 585-88; Gallier et al. Org. Lett.2009, 11, 3060-63; Wada et al. Tetrahedron 1996, 5, 1205-20; Wada et al.Chem. Lett. 1994, 145-48; Bogdanowicz-Szwed and Palasz Monatsh. Chem.1997, 128, 1157-72). It is also reported that different coordinationmodes of Eu(fod)₃ and Yb(fod)₃ may account for their different facialselectivity in HDA reaction (Cousins et al. Chem. Commun. 1997, 2171-72;Turov et al. Chemistry of Heterocyclic Compounds, 2004, 40, 986-91;Turov et al. Russ. J. Org. Chem. 2005, 41, 47-53). The high facialselectivity induced by Yb(fod)₃ may be explained by the possibility thatan extra α-face coordination to the 7,20-epoxy probably occurs to blockα-face during the activation of 1-ketone of the A-ring, andconsequently, the dienophile approaches to the heterodiene mainly fromthe less hindered β-face in an endo-selective manner. In the case ofmore oxophilic Eu(fod)₃, it is likely not only to chelate with the7,20-epoxy from α-face, but also coordinate to both 6-hydroxyl and15-ketone to form the bidentate complex from β-face, leading to theblockage of both α- and β-faces, which eventually results in the poorfacial selectivity and longer reaction time. Other catalysts such asTi(O-iPr)₄ and (±)-BINOL also promote this reaction, but the yields aremuch lower (entries 9 and 10). In addition, no reaction or decompositionwas observed when ZnCl₂ or Cu(OTf)₂ was employed as catalysts (entries 6and 8).

TABLE 4 Optimization of Cross-HDA Reaction Conditions for 8 and 9^(a)Tem- pera- ture Time Dr Yield (%)^(c) Entry Catalyst Solvent (° C.) (h)(8/9)^(b) 8 and 9 10 1 Eu(fod)₃ 1,4-dioxane^(d) Rt 72 —^(e) trace 24 2Eu(fod)₃ THF^(d) Rt 72 — trace 21 3 Eu(fod)₃ 1,4-dioxane^(d) 80 72 45:5515 62 4 Eu(fod)₃ n-butyl vinyl Rt 168 53:47 63 18 ether 5 None n-butylvinyl Rt 72 — NR^(f) 14 ether 6 ZnCl₂ n-butyl vinyl 32 72 — NR^(g) —ether 7 Yb(fod)₃ n-butyl vinyl 32 72 10:90 68 14 ether 8 Cu(OTf)₂n-butyl vinyl 32 2 — de- — ether composed 9 Ti(O—iPr)₄ n-butyl vinyl 3272 — 13 30 ether 10 (±)- n-butyl vinyl 32 72 —  8 28 BINOL ether ^(a)7(0.1 mmol), n-butyl vinyl ether (1 mL), and 10% mol of catalysts.^(b)Determined by isolated yield. ^(c)Isolated yield. ^(d)7 (1 equiv),n-butyl vinyl ether (4 equiv) and solvents (1 mL). ^(e)Not determined.^(f)No reaction. ^(g)Polymerization of vinyl ether was observed.

EXAMPLE 31 Substrate Scope of One-Pot Cross-had Reactions with VariousVinyl Ether and Vinyl Sulfide

The optimized cross-HDA reaction condition was then applied for thesynthesis of various substituted pyran-fused derivatives of 1 to explorethe generality and scope. Several different vinyl ethers as well asvinyl sulfide were employed as the dienophiles to react with 7. To avoidself-dimerization during the reaction workup, intermediate 7 wasdirectly used in the following HDA reaction without furtherpurification. From the results summarized in Scheme 4 (shown in FIG.12), 10 mol % Yb(fod)₃ was also found to be the effective catalyst andall reactions proceeded smoothly, affording the desired cycloadducts. Incases of ethyl vinyl ether, isobutyl vinyl ether, tent-butyl vinylether, 2-chloroethyl vinyl ether and allyl vinyl ether, thecorresponding cycloadducts (compounds 11-20) were obtained in total52-59% yields (2 steps) with roughly 10:90 ratios, generally similar tothat of n-butyl vinyl ether. The steric effects of the substituents onvinyl ether did not show significant difference in terms of yields anddiastereomeric ratios (Scheme 4 illustrated in FIG. 12, compounds11-16). The high selectivity for the vinyl ether double bond versus theallyl double bond was also observed in the case of allyl vinyl ether(scheme 4, compounds 17-18). Furthermore, ethyl vinyl sulfide gave aslightly increased yield with completely controlled α-face selectivityto solely achieve compound 24 after shorter reaction time in comparisonwith ethyl vinyl ether. Different from others, the poor facialselectivity (dr=55:45, α/β) was unexpectedly observed when1,4-butanediol vinyl ether was used as the dienophile. Interestingly,exchange of lanthanide catalyst from Yb(fod)₃ to Eu(fod)₃ exclusivelyled to compound 21 in 70% yield with totally controlled α-faceselectivity, and no diastereoisomer 22 was found. The switchable facialselectivity in this HDA reaction could be explained based on ourpreviously proposed reaction mode. It was speculated that the hydroxylgroup of the dienophile might perturb the weak coordination of Yb(fod)₃to the 7,20-epoxy owning to its superior chelating ability to makeα-face unblocked, which resulted in the loss of facial selectivity.Similarly, this hydroxyl group was also able to disassociate thechelating complex of Eu(fod)₃ with the 7,20-epoxy to unblock α-face, butthe more stable bidentate complex in β-face was still kept intact, andaccordingly, the dienophile approached to the heterodiene exclusivelyfrom the less hindered α-face.

EXAMPLE 32 Further Functional Group Transformations of 21 (Scheme 5)

The terminal hydroxyl group of 21 could be considered as a startingpoint for further functional group transformations to generatestructural diversity. As shown in Scheme 5, mesylation of 21 with MsClin the presence of Et₃N selectively produced intermediate 25 in 86%yield, which was followed by treatment with NaN₃ to furnish a valuableazide 26 (63%) useful for building a potential compound library.

EXAMPLE 33 One-Pot Cross-HDA Reaction of 6 with 3,4-dihydro-2H-pyran

To further explore the generality and scope of this reaction for thediversity of the ent-kaurane scaffold, 3,4-dihydro-2H-pyran was selectedas the dienophile to undergo Yb(fod)₃-catalyzed cross-HDA reaction with7. (2R,3S)-27 was obtained in 35% yield as the main cycloadduct, alongwith trace amount of (2S,3R)-28, after a long reaction time (7 days)likely through an exo-selective HDA reaction (Scheme 6). In this case,3,4-dihydro-2H-pyran approaches to the heterodiene from the β-face in anexo-selective manner to give 27 due to the enhanced steric effect of thecyclic vinyl ether with the ent-kaurane ring system.

EXAMPLE 34 Hydrolysis Reactions of Compounds 11 and 12 by 5% HCL (aq)

Considering that 3,4-dihydro-2H-pyran moieties are versatile syntheticbuilding blocks for generation of various functionalized heterocycles,carbohydrates and natural products, we inevitably became interested infurther chemical transformation based on this attractive scaffold. Asshown in Scheme 7, treatment of compound 11 with 5% HCl (aq) for 45 minreadily provided the deprotected derivative 29 in 78% yield, which wasfurther hydrolyzed with 5% HCl (aq) for another 4 h to solely yieldaldehyde 31 in 82% yield with high β-face selectivity. Acetonidedeprotection of diastereoisomer 12 under the same condition gave thecorresponding deprotected product 30, which was also prone to cleavageof the dihydropyran ring affording 31 in 60% yield (two steps). Thestructure of 31 was also well determined by ¹H and ¹³C NMR, HRMS, HMBC,HMQC and NOSEY. 31 could be used as another common building block toextend the structural diversity.

EXAMPLE 35 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S′,13aS,13bS)-2-butoxy-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-H]chromen-17-one (8) and(2S′,6aR,7S,7aR,7a′R,10aR,11S,13aS,13bS)-2-butoxy-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6₂6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4°,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(9)

A mixture of 6 (50 mg, 0.12 mmol), dimethylammonium chloride (21 mg,0.26 mmol), and paraformaldehyde (8.0 mg) in 1,4-dioxane (2 mL) wasrefluxed for 4 h. The reaction mixture was then diluted with 3 mL ofwater and extracted with 10 mL of dichloromethane three times. Theextract was washed with saturated NaHCO₃ (aq) solution (5 mL) and brine(5 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to give anoily residue. The residue was purified using silica gel column; elutionwith 60% EtOAc in hexanes afforded the desired product 7 as a colorlessgel (41 mg, 80%). ¹H NMR (300 MHz, CDCl₃): δ 6.17 (s, 1H), 6.03 (s, 1H),5.59 (s, 1H), 5.27 (s, 1H), 5.20 (d, 1H, J=12.0 Hz), 4.87 (s, 1H), 4.24(d, 1H, J=9.9 Hz), 4.01 (d, 1H, J=9.9 Hz), 3.91 (dd, 1H, J=12.0 Hz, 9.0Hz), 3.07 (d, 1H, J=9.0 Hz), 2.48 (m, 3H), 1.96 (m, 2H), 1.83 (d, 1H,J=8.7 Hz), 1.68 (m, 1H), 1.65 (s, 3H), 1.45 (m, 1H), 1.43 (m, 1H), 1.35(s, 3H), 1.25 (s, 3H), 1.00 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.6,199.0, 150.4, 141.7, 125.5, 120.8, 101.3, 95.8, 71.6, 70.0, 65.9, 59.5,55.8, 47.0 (2C), 46.6, 40.1, 32.8, 30.2, 30.1, 30.0, 25.3, 21.5, 19.0.HRMS Calcd for C₂₄H₃₀O₆: [M+H]⁺ 415.2115; found 415.2109.

To a solution of 7 (41 mg, 0.10 mmol) in n-butyl vinyl ether (1 mL) wasadded Yb(OTf)₃ (11 mg, 0.01 mmol) at rt. The resulting mixture wasstirred at 32° C. for 72 h. The reaction mixture was then diluted with 3mL of water and extracted with 10 mL of dichloromethane three times. Theextract was washed with brine (5 mL), dried over anhydrous Na₂SO₄,filtered, and evaporated to give an oily residue. The residue wasfurther purified using preparative TLC developed by 15% EtOAc in hexanesto afford the desired product 8 (3.4 mg) and 9 (31.1 mg) as colorlessamorphous gel in total 68% yield.

8: [α]²⁵ _(D) −10 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.31 (d, 1H, J=12.0 Hz), 4.89 (m, 1H), 4.85 (d, 1H,J=1.2 Hz), 4.23 (dd, 1H, J=9.6 Hz, 0.9 Hz), 4.00 (d, 1H, J=9.6 Hz), 3.89(dd, 1H, J=12.0 Hz, 8.7 Hz), 3.53 (dt, 1H, J=9.0 Hz, 6.6 Hz), 3.37 (dt,1H, J=9.6 Hz, 6.3 Hz), 3.03 (d, 1H, J=9.3 Hz), 2.49 (m, 1H), 1.86 (m,7H), 1.65 (s, 3H), 1.62 (m, 2H), 1.49 (m, 4H), 1.34 (s, 3H), 1.29 (m,2H), 1.16 (s, 3H), 1.01 (s, 3H), 0.89 (t, 3H, J=7.2 Hz). ¹³C NMR (75MHz, CDCl₃) δ 204.7, 150.9, 140.7, 119.9, 108.8, 100.9, 95.4 (2C), 72.0,70.1, 67.4, 64.1, 59.0, 56.5, 50.1, 45.2, 40.6, 40.3, 32.9, 31.8, 30.8,30.6, 30.1, 26.8, 25.3, 21.9, 20.9, 20.6, 19.5, 13.9. HRMS Calcd forC₃₀H₄₂O₇: [M +H]⁺ 515.3003; found 515.2999.

9: [α]²⁵ _(D) +118 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.34 (d, 1H, J=11.7 Hz), 4.86 (d, 1H, J=0.9 Hz), 4.58(dd, 1H, J=9.0 Hz, 1.5 Hz), 4.18 (d, 1H, J=8.7 Hz), 3.99 (d, 1H, J=9.6Hz), 3.89 (dd, 1H, J=12.0 Hz, 8.7 Hz), 3.77 (dt, 1H, J=9.3 Hz, 6.3 Hz),3.45 (dt, 1H, J=9.3 Hz, 6.3 Hz), 3.03 (d, 1H, J=9.0 Hz), 2.48 (m, 1H),1.95 (m, 7H), 1.66 (s, 3H), 1.64 (m, 2H), 1.55 (m, 4H), 1.39 (m, 2H),1.34 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.93 (t, 3H, J=7.2 Hz). ¹³CNMR (75 MHz, CDCl₃) δ 204.7, 150.9, 142.7, 120.0, 107.4, 100.9, 99.9,95.4, 72.0, 70.1, 68.7, 63.9, 58.6, 56.5, 49.8, 44.8, 40.6, 40.3, 32.9,31.7, 30.8 (2C), 30.1, 28.4, 25.9, 25.4, 21.3, 20.4, 19.3, 13.8. HRMSCalcd for C₃₀H₄₂O₇: [M +H]⁺ 515.3003; found 515.2994.

EXAMPLE 36 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-ethoxy-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,1,12,13,13a-dodecahydro-7a,13b-(epdxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6:4,5]naphtho[2,1-h]chromen-17-one(11) and(2S,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-ethoxy-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4°,5′,6′:4,5]naphtho[2,1-h]chromen-17-one (12)

With reference to FIG. 12, a mixture of 6 (50 mg, 0.12 mmol),dimethylammonium chloride (21 mg, 0.26 mmol), and paraformaldehyde (8mg) in 1,4-dioxane (2 mL) was refluxed for 4 h. The reaction mixture wasthen diluted with 3 mL of water and extracted with 10 mL ofdichloromethane three times. The extract was washed with saturatedNaHCO₃ (aq) solution (5 mL) and brine (5 mL), dried over anhydrousNa₂SO₄, filtered, and evaporated to give an oily residue. Without anypurification, the residue was directly dissolved in n-butyl vinyl ether(1 mL) in the presence of Yb(fod)₃ (11 mg, 0.01 mmol). The resultingmixture was stirred at 32° C. for 72 h. The reaction mixture was thendiluted with 3 mL of water and extracted with 10 mL of dichloromethanethree times. The extract was washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered, and evaporated to give an oily residue. Theresidue was further purified using preparative TLC developed by 15%EtOAc in hexanes to afford the desired product 11 (3.7 mg) and 12 (34.0mg) as colorless amorphous gel in total 59% yield (2 steps).

11: [α]²⁵ _(D) +8 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.30 (d, 1H, J=12.0 Hz), 4.91 (m, 1H), 4.85 (d, 1H,J=1.2 Hz), 4.23 (dd, 1H, J=9.3 Hz, 1.2 Hz), 4.00 (d, 1H, J=9.3 Hz), 3.89(dd, 1H, J=12.0 Hz, 9.0 Hz), 3.60 (dq, 1H, J=9.3 Hz, 6.9 Hz), 3.44 (dq,1H, J=9.3 Hz, 6.9 Hz), 3.03 (d, 1H, J=9.6 Hz), 2.48 (m, 1H), 1.86 (m,9H), 1.65 (s, 3H), 1.51 (m, 2H), 1.34 (s, 3H), 1.16 (s, 3H), 1.14 (t,3H, J=7.2 Hz), 1.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9,140.8, 119.9, 108.9, 100.9, 95.4, 95.2, 72.1, 70.1, 64.1, 62.9, 59.1,56.5, 50.1, 45.2, 40.6, 40.3, 32.9, 30.8, 30.6, 30.2, 26.9, 25.3, 22.1,21.0, 20.6, 15.1. HRMS Calcd for C₂₈H₃₈O₇: [M+H]⁺ 487.2690; found487.2682.

12: [α]²⁵ _(D) +102 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14(s, 1H), 5.54 (s, 1H), 5.34 (d, 1H, J=12.0 Hz), 4.86 (d, 1H, J=1.8 Hz),4.60 (dd, 1H, J=8.7 Hz, 1.8 Hz), 4.18 (d, 1H, J=9.3 Hz), 3.99 (d, 1H,J=9.3 Hz), 3.86 (dd, 1H, J=12.0 Hz, 8.7 Hz), 3.83 (dq, 1H, J=9.6 Hz, 6.9Hz) 3.53 (dq, 1H, J=9.6 Hz, 7.2 Hz), 2.50 (m, 1H), 1.97 (m, 7H), 1.67(m, 2H), 1.65 (s, 3H), 1.54 (m, 2H), 1.34 (s, 3H), 1.22 (t, 3H, J=7.2Hz), 1.17 (s, 3H), 1.03 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9,142.7, 120.0, 107.5, 100.9, 99.7, 95.4, 72.0, 70.1, 64.4, 63.9, 58.6,56.4, 49.7, 44.7, 40.6, 40.3, 32.9, 30.8 (2C), 30.1, 28.4, 25.9, 25.3,21.2, 20.4, 15.2. HRMS Calcd for C₂₈H₃₈O₇: [M+H]⁺ 487.2690; found487.2684.

EXAMPLE 37 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-7-hydroxy-2-isobutoxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epdxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(13) and(2S,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-7-hydroxy-2-isobutoxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epdxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(14)

With reference to FIG. 12, compounds 13 (3.6 mg) and 14 (31.0 mg) wereprepared in 54% yield (2 steps) by a procedure similar to that used toprepare compounds 11 and 12. The title compounds were obtained ascolorless amorphous gel.

13: [α]²⁵ _(D) +8 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.32 (d, 1H, J=12.0 Hz), 4.88 (m, 1H), 4.85 (d, 1H,J=0.9 Hz), 4.23 (d, 1H, J=10.2 Hz), 4.01 (d, 1H, J=9.9 Hz), 3.89 (dd,1H, J=12.0 Hz, 9.0 Hz), 3.25 (dd, 1H, J=8.7 Hz, 7.2 Hz), 3.15 (dd, 1H,J=8.7 Hz, 6.0 Hz), 3.03 (d, 1H, J=9.0 Hz), 2.48 (m, 1H), 1.83 (m, 9H),1.66 (s, 3H), 1.56 (m, 3H), 1.35 (s, 3H), 1.16 (s, 3H), 1.00 (s, 3H),0.85 (d, 6H, J=6.6 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9, 140.7,119.9, 108.8, 100.9, 95.5, 95.4, 74.4, 72.0, 70.1, 64.2, 59.0, 56.5,50.1, 45.2, 40.6, 40.3, 32.8, 30.8, 30.6, 30.1, 28.5, 26.8, 25.3, 21.8,20.9, 20.6, 19.5, 19.3. HRMS Calcd for C₃₀H₄₂O₇: [M+H]⁺ 515.3003; found515.3011.

14: [α]²⁵ _(D) +90 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.34 (d, 1H, J=12.0 Hz), 4.87 (d, 1H, J=1.2 Hz), 4.57(d, 1H, J=9.0 Hz), 4.17 (d, 1H, J=9.0 Hz), 3.99 (d, 1H, J=9.3 Hz), 3.89(dd, 1H, J=12.0 Hz, 9.0 Hz), 3.53 (dd, 1H, J=9.3 Hz, 6.6 Hz), 3.20 (dd,1H, J=9.3 Hz, 6.6 Hz), 3.03 (d, 1H, J=8.4 Hz), 2.50 (m, 1H), 1.94 (m,9H), 1.66 (s, 3H), 1.53 (m, 3H), 1.34 (s, 3H), 1.17 (s, 3H), 1.03 (s,3H), 0.91 (dt, 6H, J=0.6 Hz, 6.6 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 204.7,150.9, 142.7, 120.0, 107.4, 100.9, 100.0, 95.4, 75.8, 72.0, 70.1, 63.9,58.6, 56.5, 49.8, 44.7, 40.5, 40.3, 32.8, 30.8 (2C), 30.1, 28.5, 28.3,25.8, 25.4, 21.2, 20.4, 19.3 (2C). HRMS Calcd for C₃₀H₄₂O₇: [M+H]⁺515.3003; found 515.2992.

EXAMPLE 38 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(tert-butoxy)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6═,4,5]naphtho[2,1-h]chromen-17-one(15) and(2s,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(tert-butoxy)-7-hydroxy-6,6,9,9-tetrametryl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epdxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(16)

With reference to FIG. 12, compounds 15 (3.5 mg) and 16 (29.6 mg) wereprepared in 52% yield (2 steps) by a procedure similar to that used toprepare compounds 11 and 12. The title compounds were obtained ascolorless amorphous gel.

15: [α]²⁵ _(D) +10 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.13 (s,1H), 5.53 (s, 1H), 5.31 (d, 1H, J=11.7 Hz), 5.19 (s, 1H), 4.84 (s, 1H),4.18 (d, 1H, J=9.6 Hz), 3.98 (d, 1H, J=9.6 Hz), 3.87 (dd, 1H, J=12.0 Hz,9.0 Hz), 3.03 (d, 1H, J=9.0 Hz), 2.48 (m, 1H), 2.02 (m, 2H), 1.86 (m,3H), 1.66 (s, 3H), 1.64 (m, 4H), 1.53 (m, 2H), 1.34 (s, 3H), 1.68 (s,9H), 1.15 (s, 3H), 1.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 151.0,141.2, 119.8, 108.1, 100.8, 95.3, 89.8, 73.9, 72.0, 70.1, 64.4, 59.1,56.6, 50.2, 45.4, 40.3 (2C), 32.9, 30.8, 30.5, 30.1, 28.8 (3C), 28.4,25.4, 21.6, 20.8, 20.6. HRMS Calcd for C₃₀H₄₂O₇: [M+H]⁺ 515.3003; found515.3005.

16: [α]²⁵ _(D) +96 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.13 (s,1H), 5.54 (s, 1H), 5.34 (d, 1H, J=12.0 Hz), 4.86 (d, 1H, J=1.5 Hz), 4.75(dd, 1H, J=2.1 Hz, 9.0 Hz), 4.14 (d, 1H, J=9.6 Hz), 3.98 (d, 1H, J=9.9Hz), 3.88 (dd, 1H, J=12.0 Hz, 9.0 Hz), 3.03 (d, 1H, J=9.6 Hz), 2.48 (m,1H), 1.92 (m, 7H), 1.66 (s, 3H), 1.64 (m, 2H), 1.52 (m, 2H), 1.34 (s,3H), 1.23 (s, 9H), 1.17 (s, 3H), 1.04 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ204.7, 150.9, 143.2, 119.9, 107.0, 100.9, 95.4, 94.7, 75.0, 72.0, 70.1,64.2, 58.5, 56.5, 49.9, 44.7, 40.3, 40.3, 32.8, 30.9, 30.7, 30.1, 29.9,28.8 (3C), 26.7, 25.3, 21.2, 20.7. HRMS Calcd for C₃₀H₄₂O₇: [M +H]⁺515.3003; found 515.3004.

EXAMPLE 39 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(allyloxy)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epdxymethano)-7a¹,11-ethano[1,3]dioxino [4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one (17) and(2S,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(allyloxy)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epdxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(18)

With reference to FIG. 12, compounds 17 (3.5 mg) and 18 (31.8 mg) wereprepared in 57% yield (2 steps) by a procedure similar to that used toprepare compounds 11 and 12. The title compounds were obtained ascolorless amorphous gel.

17: [α]²⁵ _(D) −12 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.83 (m, 1H), 5.54 (s, 1H), 5.32 (d, 1H, J=12.0 Hz), 5.24 (dd, 1H,J=17.1 Hz, 1.8 Hz), 5.15 (dd, 1H, J=10.2 Hz, 1.5 Hz), 4.96 (t, 1H, J=1.2Hz), 4.85 (d, 1H, J=1.2 Hz), 4.23 (dd, 1H, J=9.9 Hz, 0.6 Hz), 4.08 (m,1H), 4.01 (d, 1H, J=9.9 Hz), 3.95 (m, 1H), 3.90 (dd, 1H, J=12.0 Hz, 8.7Hz), 3.04 (d, 1H, J=9.0 Hz), 2.49 (m, 1H), 1.86 (m, 9H), 1.65 (s, 3H),1.52 (m, 2H), 1.34 (s, 3H), 1.16 (s, 3H), 1.00 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 204.7, 150.9, 140.7, 134.1, 120.0, 116.7, 109.1, 100.9, 95.4,94.6, 72.0, 70.1, 67.9, 64.1, 59.0, 56.5, 50.0, 45.2, 40.6, 40.3, 32.9,30.7, 30.6, 30.1, 26.7, 25.3, 21.9, 21.0, 20.5. FIRMS Calcd forC₂₉H₃₈O₇: [M+H]⁺ Exact Mass: 499.2690; found 499.2681.

18: [α]²⁵ _(D) +106 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14(s, 1H), 5.89 (m, 1H), 5.54 (s, 1H), 5.34 (d, 1H, J=12.0 Hz), 5.28 (dd,1H, J=17.1 Hz, 1.5 Hz), 5.21 (dd, 1H, J=10.8 Hz, 1.2 Hz), 4.86 (d, 1H,J=0.3 Hz), 4.64 (d, 1H, J=8.4 Hz), 4.27 (dd, 1H, J=12.6 Hz, 5.1 Hz),4.18 (d, 1H, J=9.3 Hz), 4.05 (dd, 1H, J=12.9 Hz, 6.0 Hz), 3.99 (d, 1H,J=9.9 Hz), 3.89 (dd, 1H, J=12.0 Hz, 9.0 Hz), 3.04 (d, 1H, J=9.3 Hz),2.49 (m, 1H), 1.95 (m, 7H), 1.71 (m, 2H), 1.66 (s, 3H), 1.54 (m, 2H),1.34 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ204.7, 150.9, 142.6, 134.1, 120.0, 117.4, 107.7, 100.9, 99.0, 95.4,72.0, 70.1, 69.6, 63.9, 58.6, 56.5, 49.7, 44.8, 40.6, 40.3, 32.9, 30.8(2C), 30.1, 28.2, 25.8, 25.4, 21.3, 20.4. HRMS Calcd for C₂₉H₃₈O₇:[M+H]⁺ 499.2690; found 499.2691.

EXAMPLE 40 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-chloroethoxy)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6:4,5]naphtho[2,1-h]chromen-17-one(19) and(2S,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(2-chloroethoxy)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10A,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(20)

With reference to FIG. 12, compounds 19 (3.5 mg) and 20 (31.4 mg) wereprepared in 54% yield (2 steps) by a procedure similar to that used toprepare compounds 11 and 12. The title compounds were obtained ascolorless amorphous gel.

19: [α]²⁵ _(D) −14 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.31 (d, 1H, J=12.0 Hz), 4.98 (t, 1H, J=2.1 Hz), 4.84(d, 1H, J=1.5 Hz), 4.21 (dd, 1H, J=9.6 Hz, 1.2 Hz), 4.02 (d, 1H, J=9.3Hz), 3.89 (dd, 1H, J=12.0 Hz, 8.7 Hz), 3.77 (dt, 1H, J=10.8 Hz, 5.4 Hz),3.67 (m, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.04 (d, 1H, J=9.3 Hz), 2.49 (m,1H), 1.87 (m, 9H), 1.65 (s, 3H), 1.52 (m, 2H), 1.34 (s, 3H), 1.16 (s,3H), 1.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9, 140.6, 120.0,109.3, 100.9, 95.6, 95.4, 72.0, 70.1, 67.7, 64.0, 59.0, 56.5, 50.0,45.2, 42.7, 40.5, 40.3, 32.9, 30.7, 30.6, 30.1, 26.5, 25.3, 21.6, 21.0,20.6. HRMS Calcd for C₂₈H₃₇ClO₇: [M+H]⁺ 521.2301; found 521.2296.

20: [α]²⁵ _(D) +96 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.55 (s, 1H), 5.34 (d, 1H, J=12.0 Hz), 4.86 (d, 1H, J=1.2 Hz), 4.66(dd, 1H, J=9.0 Hz, 1.8 Hz), 4.16 (dd, 1H, J=9.6 Hz, 0.9 Hz), 4.01 (m,2H), 3.89 (dd, 1H, J=12.3 Hz, 9.0 Hz), 3.76 (m, 1H), 3.63 (t, 2H, J=6.0Hz), 3.04 (d, 1H, J=9.3 Hz), 2.49 (m, 1H), 1.96 (m, 7H), 1.68 (m, 2H),1.66 (s, 3H), 1.54 (m, 2H), 1.34 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H).¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9, 142.6, 120.1, 107.9, 100.9,100.1, 95.4, 72.0, 70.1, 69.0, 63.9, 58.6, 56.4, 49.7, 44.7, 42.8, 40.5,40.3, 32.9, 30.8 (2C), 30.1, 28.1, 25.6, 25.4, 21.2, 20.5. HRMS Calcdfor C₂₈H₃₇ClO₇: [M+H]⁺ 521.2301; found 521.2291.

EXAMPLE 41 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-7-1-Hydroxy-2-(4-hydroxybutoxy)-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(21) and(2S,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-7-hydroxy-2-(4-hydroxyburroxy)-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(22)

With reference to FIG. 12, compounds 21 (22.3 mg) and 22 (17.9 mg) wereprepared in 61% yield (2 steps) by a procedure similar to that used toprepare compounds 11 and 12. The title compounds were obtained ascolorless amorphous gel.

21: [α]²⁵ _(D) +8 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.54 (s, 1H), 5.32 (d, 1H, J=12.0 Hz), 4.91 (t, 1H, J=2.1 Hz), 4.84(s, 1H), 4.22 (d, 1H, J=8.4 Hz), 4.00 (d, 1H, J=9.3 Hz), 3.89 (dd, 1H,J=12.0 Hz, 8.4 Hz), 3.62 (m, 3H), 3.44 (m, 1H), 3.03 (d, 1H, J=9.3 Hz),2.49 (m, 1H), 1.87 (m, 9H), 1.65 (s, 3H), 1.62 (m, 5H), 1.52 (m, 2H),1.34 (s, 3H), 1.16 (s, 3H), 1.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ204.7, 150.9, 140.7, 120.0, 108.9, 100.9, 95.5, 95.4, 72.0, 70.1, 67.6,64.1, 62.6, 59.0, 56.5, 50.0, 45.2, 40.6, 40.3, 32.9, 30.7, 30.6, 30.1,30.0, 26.7, 26.4, 25.3, 21.8, 21.0, 20.6. HRMS Calcd for C₃₀H₄₂O₈:[M+H]⁺531.2952; found 531.2944.

22: [α]²⁵ _(D) +72 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.55 (s, 1H), 5.35 (d, 1H, J=12.0 Hz), 4.86 (d, 1H, J=0.9 Hz), 4.60(dd, 1H, J=9.0 Hz, 1.2 Hz), 4.17 (d, 1H, J=9.6 Hz), 3.99 (d, 1H, J=9.9Hz), 3.89 (dd, 1H, J=12.0 Hz, 9.0 Hz), 3.83 (m, 1H), 3.66 (m, 2H), 3.50(m, 1H), 3.04 (d, 1H, J=9.3 Hz), 2.50 (m, 1H), 1.94 (m, 8H), 1.66 (m,9H), 1.54 (m, 2H), 1.34 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H). ¹³C NMR (75MHz, CDCl₃) δ 204.8, 150.9, 142.7, 120.1, 107.6, 100.9, 99.8, 95.4,72.0, 70.1, 68.9, 63.9, 62.6, 58.6, 56.5, 49.7, 44.7, 40.6, 40.3, 32.9,30.8 (2C), 30.1, 29.8, 28.3, 26.4, 25.8, 25.4, 21.2, 20.5. HRMS Calcdfor C₃₀H₄₂O₈: [M+H]⁺ 531.2952; found 531.2943.

When the reaction was catalyzed by Eu(fod)₃ at rt, 21 (43.4 mg) wasobtained in 70% yield (2 steps) as the sole product.

EXAMPLE 42 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(ethylthio)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13A-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(24)

With reference to FIG. 12, compound 24 (45 mg) was prepared in 72% yield(2 steps) by a procedure similar to that used to prepare compounds 11and 12. The title compound was obtained as a colorless amorphous gel.[α]²⁵ _(D) +112 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s,1H), 5.55 (d, 1H, J=0.3 Hz), 5.34 (d, 1H, J=12.0 Hz), 4.86 (d, 1H, J=1.2Hz), 4.75 (dd, 1H, J=9.9 Hz, 1.8 Hz), 4.16 (dd, 1H, J=9.6 Hz, 1.5 Hz),3.99 (d, 1H, J=9.6 Hz), 3.89 (dd, 1H, J=12.0 Hz, 8.7 Hz), 3.03 (dd, 1H,J=9.6 Hz, 0.9 Hz), 2.67 (m, 2H), 2.50 (m, 1H), 1.97 (m, 9H), 1.65 (s,3H), 1.55 (m, 2H), 1.34 (s, 3H), 1.28 (t, 3H, J=7.2 Hz), 1.17 (s, 3H),1.04 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9, 144.6, 120.0,107.8, 100.8, 95.4, 80.1, 72.0, 70.0, 63.8, 58.7, 56.4, 49.7, 45.0,40.6, 40.3, 32.8, 30.8, 30.7, 30.1, 28.8, 26.7, 25.3, 24.7, 21.2, 20.4,15.0. HRMS Calcd for C₂₈H₃₈O₆S: [M+H]⁺ 503.2462; found 503.2449.

EXAMPLE 43 Synthesis of(3aR,3a¹R,4S,4aR,7aS,11aR,12bS,12cS,15S,15aR)-4-hydroxy-2,2,5,5-tetramethyl-16-methylene-4a,5,6,7,7a,8,9,10,11a,12c,13,14,15,15a-tetradecahydro-4H-3a,12b-(epdxymethano)-3a¹,15-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]pyrano[2,3-b]chromen-17-one(27)

Compound 27 (21 mg) was prepared in 35% yield (2 steps) by a proceduresimilar to that used to prepare compounds 11 and 12. The title compoundwas obtained as a colorless amorphous gel. [α]²⁵ _(D) +8 (c 0.10,CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.15 (d, 1H, J=0.6 Hz), 5.55 (d, 1H,J=0.6 Hz), 5.34 (d, 1H, J=12.0 Hz), 4.88 (d, 1H, J=2.1 Hz), 4.85 (d, 1H,J=1.2 Hz), 4.29 (dd, 1H, J=9.9 Hz, 1.5 Hz), 3.99 (d, 1H, J=9.6 Hz), 3.89(dd, 1H, J=12.0 Hz, 9.0 Hz), 3.75 (m, 1H), 3.65 (dt, 1H, J=11.1 Hz, 4.2Hz), 3.04 (d, 1H, J=9.6 Hz), 2.52 (m, 1H), 2.01 (m, 6H), 1.65 (m, 7H),1.51 (m, 4H), 1.34 (s, 3H), 1.17 (s, 3H), 1.02 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 204.8, 150.9, 142.0, 120.0, 106.1, 100.9, 96.5, 95.3, 72.1,70.1, 64.0, 62.6, 58.9, 56.6, 50.0, 44.8, 40.6, 40.4, 32.9, 32.8, 32.1,30.8 (2C), 30.2, 25.4, 24.3, 24.0, 21.1, 20.7. HRMS Calcd for C₂₉H₃₈O₇:[M+H]⁺ 499.2690; found 499.2686.

EXAMPLE 44 Synthesis of(2R,6aR,7S,7aR,7a¹R,10aR,11S,13aS,13bS)-2-(4-azidobutoxy)-7-hydroxy-6,6,9,9-tetramethyl-16-methylene-2,3,4,5,6,6a,7,10a,11,12,13,13a-dodecahydro-7a,13b-(epoxymethano)-7a¹,11-ethano[1,3]dioxino[4′,5′,6′:4,5]naphtho[2,1-h]chromen-17-one(26)

To a solution of compound 21 (61 mg, 0.12 mmol) in dichloromethane wasadded Et₃N (35 mg, 0.35 mmol) and MsCl (20 mg, 0.17 mmol) dropwise at 0°C. The mixture was stirred at rt overnight, and diluted with water andextracted with dichloromethane. The organic extract was washed withbrine, dried over anhydrous Na₂SO₄, filtered, and evaporated to give anoily residue. The residue was further purified using preparative TLCdeveloped by 25% EtOAc in hexanes to afford the desired product 25 as acolorless gel (62 mg, 86%). ¹H NMR (300 MHz, CDCl₃): δ 6.14 (s, 1H),5.54 (s, 1H), 5.32 (d, 1H, J=12.0 Hz), 4.89 (t, 1H, J=2.1 Hz), 4.85 (d,1H, J=1.5 Hz), 4.23 (m, 3H), 3.98 (d, 1H, J=9.3 Hz), 3.88 (dd, 1H,J=12.0 Hz, 9.0 Hz), 3.58 (dt, 1H, J=9.3 Hz, 6.3 Hz), 3.44 (dt, 1H, J=9.3Hz, 5.7 Hz), 3.01 (d, 1H, J=6.3 Hz), 3.00 (s, 3H), 2.48 (m, 1H), 1.90(m, 9H), 1.66 (m, 8H), 1.52 (m, 2H), 1.34 (s, 3H), 1.16 (s, 3H), 1.00(s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9, 140.7, 120.0, 108.9,100.9, 95.5, 95.4, 72.0, 70.1, 69.7, 66.8, 64.1, 59.0, 56.5, 50.0, 45.2,40.6, 40.3, 37.4, 32.9, 30.8, 30.6, 30.1, 26.7, 26.4, 25.7, 25.3, 21.9,21.0, 20.6. HRMS Calcd for C₃₁H₄₄O₁₀S: [M+H]⁺ 609.2728; found 609.2717.

A mixture of 25 (30 mg, 0.05 mmol) and NaN₃ (10 mg, 0.15 mmol) in thedried DMF (2 mL) was stirred at 65° C. under N₂ for 16 h. After thecompletion of the reaction, which was monitored by TLC, the mixture wasdiluted with water and extracted with dichloromethane. The organicextract was washed with brine, dried over anhydrous Na₂SO₄, filtered,and evaporated to give an oily residue, which was further purified usingpreparative TLC developed by 20% EtOAc in hexanes to afford the desiredproduct 26 (16.8 mg, 63%) as a colorless amorphous gel. 1H NMR (300 MHz,CDCl₃): δ 6.14 (s, 1H), 5.54 (d, 1H, J=0.3 Hz), 5.32 (d, 1H, J=12.0 Hz),4.90 (t, 1H, J=2.1 Hz), 4.84 (d, 1H, J=1.5 Hz), 4.22 (dd, 1H, J=9.3 Hz,1.2 Hz), 3.99 (d, 1H, J=9.6 Hz), 3.89 (dd, 1H, J=9.0 Hz, 12.0 Hz), 3.56(m, 1H), 3.42 (m, 1H), 3.27 (m, 2H), 3.04 (d, 1H, J=9.6 Hz), 2.49 (m,1H), 1.88 (m, 9H), 1.64 (m, 8H), 1.52 (m, 2H), 1.34 (s, 3H), 1.16 (s,3H), 1.01 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 150.9, 140.7, 120.0,109.0, 101.0, 95.5, 95.4, 72.1, 70.1, 67.0, 64.2, 59.0, 56.5, 51.3,50.1, 45.2, 40.6, 40.3, 32.9, 30.8, 30.6, 30.2, 26.9, 26.8, 26.1, 25.4,21.9, 21.0, 20.6. HRMS Calcd for C₃₀H₄₁N₃O₇: [M+H]⁺ 556.3017; found556.3010.

EXAMPLE 45 Synthesis of(2R,6aR,7S,8S,8aR,11S,13aS,13bS,16R)-2-ethoxy-7,8,16-trihydroxy-6,6-dimethyl-10-methylene-3,4,5,6,6a,7,8,10,11,12,13,13a-dodecahydro-8,13b-(epoxymethano)-8a,11-methanocyclohepta[3,4]benzo[1,2-H]chromen-9(2H)-one(29) and3-((2R,4aR,5S,6S,6aR,9S,11aS,11bS,14R)-5,6,14-trihydroxy-4,4-dimethyl-8-methylene-1,7-dioxododecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-2-yl)propanal(31)

To a solution of 11 (10 mg, 0.02 mmol) in THF (1.0 mL) was added 5% HClaqueous solution (0.4 mL) at rt. The resulting mixture was stirred at rtfor 45 min, and then diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 2.5% methanol in dichloromethane to affordthe desired product 29 (7.2 mg, 78%) as a colorless amorphous gel. [α]²⁵_(D) +12 (c 0.10, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ 6.18 (s, 1H), 5.87(dd, 1H, J=12.0 Hz, 4.2 Hz), 5.56 (s, 1H), 5.11 (m, 1H), 4.92 (s, 2H),4.69 (s, 1H), 4.27 (dd, 1H, J=9.6 Hz, 0.9 Hz), 3.99 (d, 1H, J=9.9 Hz),3.79 (dd, 1H, J=12.0 Hz, 9.0 Hz), 3.59 (dq, 1H, J=9.6 Hz, 6.9 Hz), 3.44(dq, 1H, J=9.6 Hz, 6.9 Hz), 3.02 (d, 1H, J=9.9 Hz), 2.44 (m, 1H), 1.97(m, 4H), 1.78 (m, 2H), 1.67 (m, 3H), 1.52 (m, 2H), 1.15 (t, 3H, J=7.2Hz), 1.13 (s, 3H), 1.00 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 206.6, 151.6,140.5, 120.9, 109.7, 97.7, 95.2, 73.5, 72.0, 64.7, 63.0, 62.5, 58.5,53.3, 45.1, 42.6, 41.4, 33.0, 30.4, 30.2, 26.9, 22.2, 20.7, 20.5, 15.1.HRMS Calcd for C₂₅H₃₄O₇: [M+H]⁺ 447.2377; found 447.2380.

To a solution of 29 (5.0 mg, 0.01 mmol) in THF (1.0 mL) was added 5% HClaqueous solution (0.2 mL) at rt. The resulting mixture was stirred at rtfor 4 h, and then diluted with water and extracted with dichloromethane.The extract was washed with saturated NaHCO₃ (aq) solution and brine,dried over anhydrous Na₂SO₄, filtered, and evaporated to give an oilyresidue. The residue was purified using preparative TLC developed by 3%methanol in dichloromethane to afford the desired product 31 (3.8 mg,82%) as a colorless amorphous gel. [α]²⁵ _(D) +172 (c 0.10, CH₂Cl₂). ¹HNMR (300 MHz, CDCl₃): δ 9.71 (t, 1H, J=1.5 Hz), 6.26 (s, 1H), 5.89 (d,1H, J=11.7 Hz), 5.65 (s, 1H), 5.41 (br s, 1H), 4.85 (s, 1H), 4.54 (br s,1H), 4.34 (d, 1H, J=10.2 Hz), 4.01 (dd, 1H, J=10.5 Hz, 1.2 Hz), 3.78(dd, 1H, J=12.0 Hz, 9.0 Hz), 3.06 (d, 1H, J=9.3 Hz), 2.59 (m, 1H), 2.43(m, 3H), 2.13 (m, 3H), 1.88 (m, 2H), 1.65 (m, 1H), 1.55 (m, 1H), 1.28(m, 1H), 1.18 (s, 3H), 0.98 (m, 1H), 0.92 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 212.9, 206.3, 201.7, 150.7, 122.3, 98.2, 73.3, 71.9, 64.5,61.5, 59.0, 50.2, 48.9, 46.6, 42.6 (2C), 41.2, 32.7, 30.7, 29.4, 24.7,21.9, 19.0. HRMS Calcd for C₂₃H₃₀O₇: [M+H]⁺ 419.2064; found 419.2071.

To a solution of 12 (5.0 mg, 0.01 mmol) in THF (1.0 mL) was added 5% HClaqueous solution (0.3 mL) at rt. The resulting mixture was stirred at rtfor 5 h, and then diluted with water and extracted with dichloromethane.The extract was washed with saturated NaHCO₃ (aq) solution and brine,dried over anhydrous Na₂SO₄, filtered, and evaporated to give an oilyresidue. The residue was purified using preparative TLC developed by 3%methanol in dichloromethane to afford the desired product 31 (2.5 mg,60%) as a colorless amorphous gel.

EXAMPLE 46(1aR,3aR,4S,4aR,4a¹R,7aR,8S,10aS,10bS,10cS)-4-hydroxy-3,3,6,6-tetramethyl-13-methylenedecahydro-1aH-4a,10b-(epoxymethano)-4a¹,8-ethanooxireno[2′,3′:5,6]phenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-9)

To solution of CYD-7-8 (16 mg, 0.04 mmol) in dichloromethane (4 mL) wasadded m-CPBA (9.0 mg, 0.04 mmol) at 0° C. The resulting mixture wasstirred at rt for 1 h. After that, the reaction mixture was diluted withwater and extracted with dichloromethane. The extract was washed withsaturated NaHCO₃ (aq.) solution and brine, dried over anhydrous Na₂SO₄,filtered, and evaporated to give an oily residue. The residue wasfurther purified using preparative TLC developed by 50% EtOAc in hexaneto afford the desired product CYD-7-9 as a colorless gel (13 mg, 78%).¹H NMR (600 MHz, CDCl₃) δ 6.18 (s, 1H), 5.90 (s, 1H), 5.58 (br s, 1H),4.83 (s, 1H), 4.14 (d, 1H, J=9.6 Hz), 4.02 (d, 1H, J=9.6 Hz), 3.82 (brs, 1H), 3.25 (br s, 1H), 3.08 (d, 1H, J=9.0 Hz), 2.58 (m, 1H), 2.55 (m,1H), 2.09 (m, 1H), 1.83 (m, 3H), 1.72 (m, 1H), 1.65 (s, 3H), 1.52 (d,1H, J=15.0 Hz), 1.34 (s, 3H), 1.19 (d, 1H, J=7.8 Hz), 1.08 (s, 3H), 1.04(s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 204.4, 150.2, 120.7, 101.4, 95.3,71.9, 70.0, 64.9, 55.7, 54.4, 53.1, 52.3, 45.5, 40.4, 40.2, 36.0, 32.4,30.3, 30.1 (2C), 25.5, 23.5, 16.6.

EXAMPLE 47(1aR,3aR,4S,5S,5aR,8S,10aS,10bS,10cS,13R)-4,5,13-trihydroxy-3,3-dimethyl-7-methylenedecahydro-1aH-5,10b-(epoxymethano)-5a,8-methanocyclohepta[7,8]naphtho[1,2-b]oxiren-6(2H)-one(CYD-7-3-1) and(1S,2S,4aR,5S,6S,6aR,9S,11aS,11bS,14R)-1,2,5,6,14-pentahydroxy-4,4-dimethyl-8-methylenedecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-7(8H)-one(CYD-7-23-2)

To a solution of CYD-7-9 (10 mg, 0.024 mmol) in a mixture of MeOH (2 mL)and CH₂Cl₂ (0.5 mL) was added 5% HCl aqueous solution (0.5 mL) at rt.The resulting mixture was stirred at rt for 2 hrs. After that, thereaction mixture was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 10% methanol in dichloromethane to affordthe desired product CYD-7-23-1 (4 mg, 44.4%) as a colorless gel andCYD-7-23-2 (5 mg, 52.8%) as a white solid, respectively. It was notedthat longer reaction time resulted in CYD-7-23-2 as solely product.CYD-7-23-1: ¹H NMR (600 MHz, CDCl₃) δ 6.21 (s, 1H), 6.04 (d, 1H, J=12.0Hz), 5.60 (d, 1H, J=0.9 Hz), 5.18 (br s, 1H), 4.90 (d, 1H, J=0.9 Hz),4.46 (br s, 1H), 4.10 (m, 2H), 3.69 (dd, 1H, J=8.4 Hz, 11.7 Hz), 3.25(m, 1H), 3.06 (m, 1H), 2.58 (d, 1H, J=4.2 Hz), 2.50 (m, 1H), 2.05 (m,1H), 1.76 (m, 4H), 1.52 (m, 1H), 1.20 (dd, 1H, J=0.6 Hz, 8.1 Hz), 1.05(s, 3H), 1.02 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 206.3, 150.9, 121.6,97.6, 73.5, 72.0, 65.6, 61.7, 53.8, 53.3, 52.6, 48.9, 42.8, 40.0, 36.6,32.4, 30.0, 29.6, 23.2, 16.8.

CYD-7-23-2: ¹H NMR (600 MHz, CD₃OD+CD₃Cl) δ 6.16 (s, 1H), 5.58 (s, 1H),4.89 (d, 1H, J=1.2 Hz), 4.74 (dd, 1H, J=1.8 Hz, 10.2 Hz), 4.44 (br s,1H), 4.17 (m, 1H), 4.00 (d, 1H, J=1.2 Hz, 10.2 Hz), 3.85 (d, 1H, J=6.0Hz), 3.50 (d, 1H, J=2.4 Hz), 3.04 (d, 1H, J=9.6 Hz), 2.54 (m, 1H), 2.26(dd, 1H, J=4.2 Hz, 15.0 Hz), 2.20 (m, 1H), 1.87 (m, 1H), 1.79 (m, 2H),1.67 (m, 2H), 1.38 (s, 3H), 1.13 (s, 3H).

EXAMPLE 48(1aR,2R,3aR,4S,4aR,4a¹R,7aR,8S,10aS,10bS,10cS)-2,4-dihydroxy-3,3,6,6-tetramethyl-13-methylenedecahydro-1aH-4a,10b-(epoxymethano)-4a¹,8-ethanooxireno[2′,3′:5,6]phenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-19)

To a solution of CYD-7-15 (20 mg, 0.049 mmol) in dichloromethane (4 mL)was added m-CPBA (9.4 mg, 0.054 mmol) at 0° C. The resulting mixture wasstirred at rt for 1 h. After that, the reaction mixture was diluted withwater and extracted with dichloromethane. The extract was washed withsaturated NaHCO₃ (aq.) solution and brine, dried over anhydrous Na₂SO₄,filtered, and evaporated to give an oily residue. The residue wasfurther purified using preparative TLC developed by EtOAc to afford thedesired product CYD-7-19 as a colorless gel (15 mg, 72%). ¹H NMR (600MHz, CD₃Cl) δ 6.20 (s, 1H), 5.61 (d, 1H, J=0.6 Hz), 5.44 (d, 1H, J=12.6Hz), 4.82 (d, 1H, J=1.2 Hz), 4.11 (m, 1H), 4.01 (m, 1H), 3.83 (m, 1H),3.60 (m, 1H), 3.54 (m, 1H), 3.10 (d, 1H, J=9.0 Hz), 2.83 (d, 1H, J=3.6Hz), 2.58 (m, 1H), 2.17 (m, 1H), 2.04 (m, 1H), 1.84 (m, 2H), 1.70 (m,1H), 1.65 (s, 3H), 1.35 (s, 3H), 1.14 (s, 3H), 0.98 (s, 3H). ¹³C NMR(150 MHz, CDCl₃) δ 204.2, 150.1, 121.0, 101.4, 95.3, 71.5, 70.9, 69.9,64.7, 55.6 (2C), 47.2, 45.6, 40.3, 37.3, 35.9, 30.1 (2C), 25.5, 25.1,21.4, 16.6.

EXAMPLE 49(1aR,2R,3aR,4S,5S,5aR,8S,10aS,10bS,10cS,13R)-2,4,5,13-tetrahydroxy-3,3-dimethyl-7-methylenedecahydro-1aH-5,10b-(epoxymethano)-5a,8-methanocyclohepta[7,8]naphtho[1,2-b]oxiren-6(2H)-one(CYD-7-27)

To a solution of CYD-7-19 (12 mg, 0.028 mmol) in a mixture of MeOH (2mL) and CH₂Cl₂ (0.5 mL) was added 5% HCl aqueous solution (0.5 mL) atrt. The resulting mixture was stirred at rt for 2 hrs. After that, thereaction mixture was diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO₃ (aq.)solution and brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by 5% methanol in dichloromethane to affordthe desired product CYD-7-27 (8 mg, 74%) as colorless gel. ¹H NMR (600MHz, CD₃Cl) δ 6.23 (s, 1H), 6.04 (d, 1H, J=12.0 Hz), 5.63 (d, 1H, J=0.6Hz), 5.37 (br s, 1H), 5.30 (s, 1H), 4.90 (d, 1H, J=1.2 Hz), 4.52 (br s,1H), 4.12 (dd, 1H, J=1.8 Hz, 10.2 Hz), 4.04 (dd, 1H, J=1.2 Hz, 10.2 Hz),3.72 (dd, 1H, J=8.4 Hz, 12.0 Hz), 3.62 (dd, 1H, J=6.0 Hz, 8.4 Hz), 3.55(dd, 1H, J=3.6 Hz, 6.0 Hz), 3.08 (d, 1H, J=9.0 Hz), 2.83 (d, 1H, J=3.6Hz), 2.52 (m, 1H), 2.19 (d, 1H, J=8.4 Hz), 2.02 (m, 1H), 1.90 (m, 1H),1.72 (m, 3H), 1.37 (d, 1H, J=8.4 Hz), 1.11 (s, 3H), 0.98 (s, 3H). ¹³CNMR (150 MHz, CDCl₃) δ 206.2, 150.7, 121.9, 97.6, 73.0, 72.1, 70.6,65.3, 61.6, 55.8, 55.7, 48.9, 46.8, 42.7, 37.3, 36.5, 29.5, 24.7, 21.1,16.7.

EXAMPLE 50(3S,3aR,3a¹R,6aR,7S,7aR,10S,11S,11aS,11bS)-10-azido-7,11-dihydroxy-5,5,8,8-tetramethyl-15-methylenedecahydro-1H-6a,11a-(epoxymethano-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-42)

To a solution of CYD-7-23-1 (25 mg, 0.062 mmol) in a mixture of ethanol(2 mL) and water (2 mL) was added NH₄Cl (7 mg, 0.124 mmol) and NaN₃ (32mg, 0.496 mmol) at rt. The resulting mixture was stirred at 85° C. for16 hrs. After that, the reaction mixture was diluted with water andextracted with dichloromethane. The extract was washed with brine, driedover anhydrous Na₂SO₄, filtered, and evaporated to give an oily residue.The residue was purified using preparative TLC developed by 5% ethylacetate in dichloromethane to afford the desired product CYD-7-42 (10mg, 64%), and 11 mg of CYD-7-23-1 was recovered. ¹H NMR (600 MHz, CD₃Cl)δ 6.19 (s, 1H), 6.02 (d, 1H, J=12.0 Hz), 5.59 (s, 1H), 4.78 (s, 1H),4.48 (d, 1H, J=10.2 Hz), 3.99 (dd, 1H, J=7.2 Hz, 12.0 Hz), 3.83 (m, 2H),3.36 (s, 1H), 3.09 (d, 1H, J=9.0 Hz), 2.54 (m, 1H), 2.25 (m, 1H), 1.96(m, 2H), 1.77 (m, 2H), 1.68 (m, 2H), 1.66 (s, 3H), 1.62 (d, 1H, J=6.6Hz), 1.37 (s, 3H), 1.35 (s, 3H), 1.23 (s, 3H).

EXAMPLE 51 (3S,3aR,3a¹R,6aR,7S,7aR,10S,11S,11aS,11bS)-7,11-dihydroxy-5,5,8,8-tetramethyl-15-methylene-10-(4-phenyl-1H-1,2,3-triazol-1-yl)decahydro-1H-6a,11a-(epoxymethano)-3,3a¹-ethanophenanthro[1,10-de][1,3]dioxin-14-one(CYD-7-54)

Copper (I) iodide (3.8 mg, 0.02 mmol) was added to a solution ofCYD-7-42 (9 mg, 0.02 mmol) and phenyl acetylene (2.4 mg, 0.024 mmol) inacetonitrile (2 mL). The reaction mixture was stirred at rt for 16 hrs.After that, the reaction mixture was diluted with water and extractedwith dichloromethane. The extract was washed with brine, dried overanhydrous Na₂SO₄, filtered, and evaporated to give an oily residue. Theresidue was purified using preparative TLC developed by 5% ethyl acetatein dichloromethane to afford the desired product CYD-7-54 (4 mg, 65%),and 4 mg of CYD-7-42 was recovered. ¹H NMR (600 MHz, CD₃Cl) δ 7.75 (m,3H), 7.39 (m, 3H), 6.19 (s, 1H), 5.59 (s, 1H), 5.57 (d, 1H, J=12.0 Hz),4.82 (d, 1H, J=1.2 Hz), 4.60 (m, 1H), 4.43 (m, 1H), 4.00 (m, 3H), 3.07(d, 1H, J=9.0 Hz), 2.99 (m, 1H), 2.50 (m, 1H), 2.33 (m, 1H), 2.18 (d,1H, J=7.2 Hz), 1.88 (m, 2H), 1.70 (m, 2H), 1.63 (s, 3H), 1.34 (s, 3H),1.30 (s, 3H), 1.17 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 205.1, 150.6,147.5, 130.1, 128.9 (2C), 128.4, 125.6 (2C), 120.4, 119.5, 101.1, 95.3,72.4, 70.1, 68.7, 66.1, 62.0, 55.8, 54.4, 45.3, 40.8, 40.4, 33.9, 32.6,30.4, 30.1, 29.7, 27.2, 25.4, 18.3.

EXAMPLE 52 Synthesis of(3S,4aR,5S,6aR,9S,11aS,11bS,14R,E)-5,14-dihydroxy-2-(methoxymethylene)-4,4-dimethyl-8-methyleneoctahydro-1H-3,11b-(epoxymethano)-6A,9-methanocyclohepta[a]-naphthalene-1,6,7(2H,8H)-trione

To a solution of 10 (5 mg, 0.011 mmol) in a mixture of MeOH (2 mL) andCH2Cl2 (0.5 mL) was added 5% HCl aqueous solution (0.2 mL) at roomtemperature. The resulting mixture was stirred at room temperature for 2h. The reaction mixture was then diluted with water and extracted withdichloromethane. The extract was washed with saturated NaHCO3 (aqueous)solution and brine, dried over anhydrous Na2SO4, filtered, andevaporated to give an oily residue. The residue was purified usingpreparative TLC developed by EtOAc to afford the desired product 13 as acolorless amorphous gel (3.5 mg, 78%). [α]25 D −110 (c 0.10, CH2Cl2);HPLC purity 98.3% (tR=14.58 min); 1H NMR (300 MHz, CDCl3) δ 7.59 (s,1H), 6.18 (s, 1H), 5.47 (s, 1H), 4.67 (m, 2H), 4.43 (d, 1H, J=0.9 Hz),4.33 (s, 1H), 4.22 (m, 1H), 3.94 (s, 3H), 3.91 (m, 1H), 3.09 (m, 1H),2.92 (m, 1H), 1.62 (m, 3H), 1.57 (m, 1H), 1.52 (s,3H), 0.99 (s, 3H); 13CNMR (75 MHz, CDCl3) δ 205.5, 201.4, 196.7, 156.3, 146.0, 118.6, 115.4,75.1, 74.2, 71.7, 66.3, 62.1, 61.5, 51.7, 51.0, 45.3, 42.0, 38.2, 30.9,28.5, 21.8, 20.1; HRMS calcd for C22H27O7, [M+H]+ 403.1751; found403.1768.

EXAMPLE 53 Synthesis of(3S,4aR,5S,6aR,9S,11aS,11bS,14R,Z)-5,14-dihydroxy-2-(hydroxymethylene)-4,4-dimethyl-8-methyleneoctahydro-1H-3,11b-(epoxymethano)-6a,9-methanocyclohepta[a]-naphthalene-1,6,7(2H,8H)-trione

To a solution of 10 (15 mg, 0.035 mmol) in THF (2 mL) was added 5% HCl(aqueous) solution (0.3 mL) at room temperature. The resulting mixturewas stirred at room temperature for 4 h. The reaction mixture was thendiluted with water and extracted with dichloromethane. The extract waswashed with saturated NaHCO3 (aqueous) solution and brine, dried overanhydrous Na2SO4, filtered, and evaporated to give an oily residue. Theresidue was purified using preparative TLC developed by 5% methanol indichloromethane to afford the desired product 14 as a pale pinkamorphous gel (11 mg, 80%). [α]25 D −104 (c 0.1, CH2Cl2); HPLC purity96.6% (tR=4.47 min); 1H NMR (300 MHz, CDCl3) δ 7.99 (br s, 1H), 7.13 (s,1H), 6.26 (s, 1H), 5.49 (s, 1H), 4.61 (d, 1H, J=6.0 Hz), 4.54 (d, 1H,J=4.5 Hz), 4.47 (s, 1H), 3.83 (m, 4H), 3.11 (d, 1H, J=1.2 Hz), 3.05 (d,1H, J=3.9 Hz), 1.89 (m, 1H), 1.75 (m, 2H), 1.57 (m, 2H), 1.48 (s, 3H),0.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 205.1, 200.4, 199.4, 160.1,144.8, 120.3, 113.2, 71.6, 65.8, 60.9, 51.4, 50.6, 45.6, 41.2, 38.7,31.1, 29.6 (2C), 22.5, 20.0. HRMS calcd for C21H25O7, [M+H]+ 389.1595;found 389.1591.

EXAMPLE 54 Synthesis of Aziridine Derivatives of Oridonin

TABLE 1 Optimization of oridonin-based aziridination conditions

Aminating Catalyst/ Temp./ Entries agents/eqv. eqv. Time Result 1DPH/1.1 eqv. Rh₂(esp)₂/ r.t./24 h CYD-6-79 (28%) 5% mmol YD-3-36 (54%) 2DPH/2.2 eqv. Rh₂(esp)₂/ r.t./24 h CYD-6-79 (trace) 5% mmol YD-3-36 (69%)3 DPH/4.4 eqv. Rh₂(esp)₂/ r.t./24 h CYD-6-79 (NA) 5% mmol YD-3-36 (71%)4 DPH/4.4 eqv. Rh₂(esp)₂/ 50° C./ CYD-6-79 (NA) 5% mmol 24 h YD-3-36(66%) 5 DPH/4.4 eqv. Rh₂(esp)₂/ 50° C./ CYD-6-79 (NA) 5% mmol >48 hYD-3-36 (56%) 6 DPH/2.2 eqv. Rh₂(OAc)₄/ r.t./24 h CYD-6-79 (trace) 5%mmol YD-3-36 (68%) 7 DPH/2.2 eqv. Rh₂(TPA)₄/ r.t./24 h CYD-6-79 5% mmol(predominance) YD-3-36 (trace) 8 DPH/2.2 eqv. Rh₂(R-DOSP)₄/ r.t./24 hCYD-6-79 5% mmol (predominance) YD-3-36 (NA) 9 DPH/2.2 eqv.Rh₂(S-DOSP)₄/ r.t./24 h CYD-6-79 5% mmol (predominance) YD-3-36 (NA)

The invention claimed is:
 1. An oridonin derivative compound having thegeneral formula of Formula IIb:

where R³ and R⁴ are independently hydrogen, hydroxy, methyl, ethyl,C3-C5 alkyl, C1-C5 hydroxyalkyl, a substituted or unsubstituted aryl, ora substituted or unsubstituted heteroaryl; where R⁵, R⁶, and R⁷ areindependently hydrogen, oxo, nitro, halo, mercapto, cyano, azido, amino,imino, azo, sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, hydroxyl,NR⁸R⁹, C1-C6 carboxyl, C1-C6 hydroxyalkyl, C1-C6 aldehyde, C2-C6 ketone,C1-C6 ester, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6alkenyl, C1-C6 alkylsulfonyl, substituted or unsubstituted 3 to 8membered cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted triazole,substituted or unsubstituted 3 to 8 membered spiro-cycloalkyl, orsubstituted or unsubstituted 3 to 8 membered spiro-heterocycle, whereinR⁶ and R⁷ cannot be hydrogen when R⁵ is oxo; and R⁸ and R⁹ areindependently hydrogen, oxo, nitro, halo, mercapto, cyano, azido, amino,imino, azo, sulfonyl, sulfinyl, sulfo, thioyl, methyl, ethyl, hydroxyl,C1-C6 carboxyl, C1-C6 hydroxyalkyl, C1-C6 aldehyde, C2-C6 ketone, C1-C6ester, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkenyl,C1-C6 alkylsulfonyl, substituted or unsubstituted 3 to 8 memberedcycloalkyl, substituted or unsubstituted 3 to 8 membered heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted triazole, substituted orunsubstituted 3 to 8 membered spiro-cycloalkyl, or substituted orunsubstituted 3 to 8 membered spiro-heterocycle; wherein the A ring hasa double bond between positions 1 and 2, or a double bond betweenpositions 2 and
 3. 2. The compound of claim 1, wherein R⁵, R⁶, or R⁷ isoxo.
 3. The compound of claim 2, wherein the A ring has a double bondbetween positions 2 and
 3. 4. The compound of claim 1, wherein the Aring has a double bond between positions 1 and
 2. 5. The compound ofclaim 1, wherein R⁵, R⁶, or R⁷ are nitro, cyano, azido, amino, imino,azo, NR⁸R⁹, substituted or unsubstituted 3 to 8 membered N containingheterocycle, or substituted or unsubstituted 3 to 8 membered Ncontaining heteroaryl, wherein R⁸ and R⁹ are independently hydrogen orC1-C4 alkyl.
 6. The compound of claim 1, wherein the compound isCYD-6-92 having the formula